PT88226B - PREPARATION PROCESS FOR PYRROLOISOQUINOLINS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

Pyrrolo[2,1-a]isoquinoline derivatives of the formula: <CHEM> wherein R<1> and R<2> each represent cycloalkyl or alkyl, alkenyl or alkynyl which may be halogen-substituted, or optionally substituted aryl or heteroaryl, X represents ethylene or vinylene, R<3> represents a group of the formula: -Y-CH2-CH(OH)-CH2-COOR<5> II wherein Y represents carbonyl or hydroxymethylene and R<5> represents hydrogen or optionally substituted alkyl, or R<3> represents a lactone ring, and the symbols R<4> represent hydrogen, halogen, optionally substituted alkyl, alkenyl or alkynyl, optionally substituted aryl or heteroaryl, or a group of the formula R<6>O-, wherein R<6> represents alkyl, aryl or arylalkyl have useful pharmaceutical properties.

Description

MSMÓRTA D3SCRITIVA

The present invention relates to the preparation of new derivatives pyrr olo / ^- 2, l-a_27is oquinolina therapeutically useful pharmaceutical compositions containing them and their use as pharmaceuticals.

Pyrrole derivatives / ^- 2,1 — a / 7isoquinoline are compounds of the formula I, presented at the end of this specification.

2 cation, where R and R, which may be the same or preferably different, each represent a cycloalkyl group containing 3 to 8 carbon atoms, or represent a straight or branched chain alkyl, alkenyl or alkynyl group containing up to 6 carbon atoms, which can be replaced by up to 3 halogen atoms, preferably chlorine or fluorine, or an aryl group, preferably phenyl, optionally substituted heteroaryl, X represents an ethylene or vinyl group, preferably a group vinylene in E configuration, R ³ represents a group of general formula II

-Y-CH ₂ -CH (OH) -CH ₂ -COOR II where Y represents a carbonyl or hydroxymethylene group and R represents a hydrogen atom or an optionally substituted alkyl group, containing up to 6 carbon atoms, or R ³ represents a lactone ring of general formula III indicated at the end of the specification, and the same or different R ⁴ symbols each represent a hydrogen or halogen atom (ie fluorine, chlorine, bromine or iodine) or represent an alkyl group, alkenyl or alkynyl, optionally substituted, straight or branched chain containing up to 6 carbon atoms, or an aryl group, preferably phenyl, or an optionally substituted heteroaryl group, or a group of formula R ^ o-, where 6

R represents a straight or branched chain alkyl group containing up to 6 carbon atoms, an aryl group, e.g. ex. phenyl or an aralkyl group containing 1 or 2 carbon atoms in the alkyl part, e.g. ex. benzyl or phenethyl, and their pharmaceutically acceptable salts when R ³ represents a hydrogen atom, for example alkali metal, alkali metal salts

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-5/7

-x calino-earth, ammonium and amine.

It should be understood that when reference is made in this specification to compounds of formula I, it is intended to also mention, where the context permits, their pharmaceutically acceptable salts.

The substituted alkyl, alkenyl or alkynyl groups, in the definition of formula I and unless otherwise specified, preferably contain up to 3 substituents chosen from halogen atoms, preferably fluorine or chlorine, and straight chain alkoxy and alkylthio groups or branched, each containing up to 6 carbon atoms.

The aryl and heteroaryl groups and moieties substituted in the definition of formula I preferably contain one or more substituents chosen from halogen atoms, preferably fluorine or chlorine, cycloalkyl and cycloalkenyl groups each containing 4 to 8 carbon atoms, groups alkyl, alkenyl or alkynyl, optionally substituted, straight or branched chain, containing up to 6 carbon atoms, hydroxy groups, alkoxy groups, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl and alkanoyl, straight or branched chain, each containing , up to 6 carbon atoms and aryl groups, preferably phenyl, and heteroaryl, optionally substituted.

As those skilled in the art can observe the compounds of formula I can exist in various isomeric forms, for example diastereoisomeric forms, and all of these forms and mixtures thereof are included within the scope of the invention. However, when R ³ represents a group of formula II and Y represents a hydroxymethylene group, the erythro form is preferred. When R ³ represents a group of formula III, the preferred form has the hydroxy group attached to the lactone ring in the trans configuration with respect to the rest of the molecule.

Preferably the lactone ring of formula III has the (4R, 6S) configuration.

The compounds of the general formula shown in Figure Γ pos. have useful pharmacological properties, some of which are useful as

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Case 1111 / PT intermediates for the preparation of other therapeutically useful compounds, for example, other compounds of formula I, described below in this specification.

For example, these compounds lower blood cholesterol and low density lipoprotein concentrations. Thus, they are useful in the prevention or treatment of hypercholesterolemic and hyperlipoproteinemic states, atherosclerosis and associated conditions such as angina, myocardial infarction, cerebral vascular occlusion, arterial aneurysm, peripheral vascular disease, recurrent pancreatitis and xanthomas.

Particularly important are classes of compounds of formula I that show one or more of the following typical characteristics:

2 (i) one of R and R, preferably R _f represents an aryl or heteroaryl group, optionally substituted more particularly a substituted or unsubstituted phenyl group, for example, a phenyl group substituted with a halogen atom, eg an atom fluorine, especially in the 4 1 2 position of the phenyl group, and the other between R and R, preferably R ¹ , represents a cycloalkyl group containing 3 to 8 carbon atoms or a straight chain alkyl, alkenyl or alkynyl group or branched, containing up to 6 carbon atoms, which can be replaced by up to 3 halogen atoms, preferably chlorine or fluorine, more particularly a straight or branched chain alkyl group, for example, a methyl, ethyl group or, preferably , isopropyl;

(ii) Y represents a hydroxymethylene group;

(iii) r5 represents a hydrogen atom or a methyl or ethyl group; and / or (iv) all R ⁴ symbols represent hydrogen atoms;

the other symbols being defined as above and, more particularly, their pharmaceutically acceptable salts, in particular the alkali metal salts, e.g. ex. sodium.

Important compounds of formula I include the following

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tes:

THE:

3: 2 mixture of erythro- and threo - diastereoisomers of (E) -3,5-dihydroxy-7- (3-isopropyl-phenylpyrrolo / ^-2, l-a_7isoquinolin-2-yl) hept-6-enoate methyl;

B:

2: 1 mixture of diastereomers erythro and (E) -3,5-dihydroxy-7- (3-isopropyl1-1-phenylpyrrole // 2, 1-a27isoquinolin-2-yl) -hept-6-enoate sodium;

Ç :

mixture of diastereoisomers erythro and (E) -3,5-dihydrox i-7— (3 —isopropyl-1-phenylpyrrole / ~ 2, 1-a7 isoquinolin-2-yl) _ hept — 6-enoate ethyl;

D:

(E) -3-h idroxy — 7- (3-isopropyl1-1-phenylpyrrole / 2,1-alpha-7-isoquinolin-2-yl) -5-oxo-hept-6-enoate;

AND:

(E) -3-hydroxy-7- (3-isopropyl 1-1— phenylpyrrole / ~ 2 _# 1-a _Tisoquinolin-2-yl) -5-oxo-hept-6-enoic acid;

F:

3,5-dihydroxy-7- (3-isopropyl1-1-phenylpyrrole / ^- 2,1-alpha-isoquinolin-2-yl) heptanoic acid;

G:

1: 2 mixture of 4-h idr oxy-62- (3-isopropyl-1-phenylpyrr0O0 / 72, l-a_7isoquinolin-2-i1) ethyl is 7-3,4,5 6- (tetrahydro) -2H-pyran-2-one;

H:

(E) ethyl -3,5-dihydride-7-f 3 -methyl 1-1-phenylpyrrole / ^- 2,1-aJ / oquinolin-2-yl) hept-6-enoate;

I:

(E) -3,5-dihydroxy-7- (3-methyl-1-phenylpyrrole / ~ 2, 1-a / 7isoqui68 073

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7 ^

IU -8nolin-2-yl) sodium hept-6-enoate;

J:

(Ej -3,5-dihydro ox i-7 - 3-ethyl-1- (4-fluorophenyl) pyrrole / 2, 1-α (7isoquinolin-2-ylJhept-6-enoate;

K:

(E) -3,5-d i -hydr oxy-7- ^ 3-ethyl-1- (4-fluorophenyl) pyrrole // 2,1,1-isoisoquinolin-2-yl ^ hept-6-enoate;

L:

3: 2 mixture of erythro diastereoisomers and (E) -3,5-dihydroxy-7-1-isopropyl-3- (4-fluorophenyl) pyrrolo Z72,1-aJ. ethyl isoquinolin-2-yl-hept — 6-enoate;

M:

mixture 3: 2 of diastereomers erythro and threus of (E) -3,5-dihydroxy-7- 1-isopropyl-3- (4-fluorophenyl) pyrrole / ^- 2, la / 7is oquinolin-2-yl hept- 6-sodium enoate;

N:

(E) -3,5-dihydroxy-7- | .3-isopropyl-1- (4-fluorophenyl) pyrrole, ethyl-1-oquinolin-2-yl-hept-6-enoate;

AT:

erythro- (E) -3,5-dihydroxy-7- 3-isopropyl1-1— (4-fluorophenyl) pyrrole / 72,1-ethylisoquinolin-2-yl-hept-6-enoate;

NB:

threo- (E) -3 _r 5-dihydroxy-7-3-isopropyl-1— (4-fluorophenyl) pyrrole / 7 ”2, 1-7isoquinolin-2-yl] hept-6-enoate;

0:

3: 2 mixture of diastereoisomers erythro and (E_) - 3,5-dihydroxy-7 - 3-isopropyl-1- (4-fluorophenyl) pyrrole / 72,1-a77— isoquinolin-2-yl hept -6-sodium enoate;

OA:

erythro- (E) -3 _f 5-dihydroxy-7- {3-isopropyl — 1— (4-fluorophenyl) -pyrrole / 72,1-a_ (7isoquinolin-2— yl I hept — 6-enoate ;

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-90B:

threo- (E) -3,5-dihydroxy-7- {3-isopropyl-1- (4-fluorophenyl) pyrrole / ~ 2,1-a-7isoquinolin-2-yl hept-6-enoate;

P:

(E) -3 -h idr ox i-7 - 3-isopropyl 1-1- (4-fluorophenyl) pyrrole / 2 ~ 2,

1-a / ^s 7i oquinolin-2 - yl ^ j -5-oxo-hept-6-enoate; and Q:

(E) -3-hydroxy-7-3-isopropyl 1-1— (4-fluoropheni) pyrrole / 72,1-a / 7isoquinolin-2-ylJ -5-oxo-hept-6-enoate.

Letters A to Q are assigned to compounds for easy reference throughout this specification.

compound B is of particular importance, especially its erythro component.

In the tests, the compounds of formula I show good results as competitive inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) -reductase and, consequently, are inhibitors of cholesterol biosynthesis.

For example, in the assays, the compounds produced inhibition of the in vitro HMG CoA hepatic microsomal rat reductase activity as shown in Table I.

In the table, the concentrations of the tested compounds are expressed in micrograms / ml.

TABLE I

Compound Concentration % Inhibition B 20.0 98 6, 4 91 2.0 81 1.6 72 0.4 44 0.2 43 Hi 28 0.025 16

Cont

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-10 TABLE I (Cont.)

Compound Concentration Inhibition AND 20.0 6.7 2, 2 90 71 50 G 20.0 44 6.7 38 H 20.0 70 6.66 54 2.22 33 0.74 22 0.24 26 I 20.0 85 6.65 68 2.22 46 0.74 35 0.25 39 0.082 44 K 6, 66 2.22 0.74 0.24 0.082 0.0274 95 86 68 46 33 27

Cont.

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-11 TABLE I (Cont.)

Compound Concentration % Inhibition M 20 „0 98 6.66 96 2.22 90 0.74 78 0.22 65 0.2 74 0.066 69 0.022 63 0.0074 46 0.0025 33 N 2.22 95 0.74 87 0.25 74 0.082 61 0.0274 55 0.0091 44 0 20.0 99 6, 66 97 2.22 92 0.74 81 0.24 69 OA 2.22 95 0.74 87 0.24 74 0.082 63 0.0274 51 0.0091 43 0.00304 37

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..4

F

TABLE I (Cont.)

Compound Concentration % Inhibition OB 2, 2 2 70 0.74 53 0.25 38 0.082 29 0.0274 21 Q 6, 66 89 2.22 70 0.74 45 0.24 22 0.082 8

In in vivo rat tests, doses of compound B produced inhibition of cholesterol biosynthesis, as shown in Table II. In the table, the doses are expressed in mg / kg of the animal's body weight.

TABLE II

Dose % Inhibition 10.0 91 3.33 77 1/11 67

The compounds of formula I and the intermediates for their preparation can be prepared by applying or adapting methods similar to those described below in the Examples and Reference Examples.

Optionally the reactions can be carried out in an inert atmosphere.

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For example, according to a characteristic of the invention, compounds of formula I where R represents a group of formula II where Y represents a hydroxymethylene group and R represents an optionally substituted alkyl group, containing 12 4 to 6 atoms of carbon, and R, R, R and X are defined as above, are prepared by the reduction of compounds of formula g and 12 4 ral IV, indicated at the end of this specification where R, R, R and

X are defined as above and R represents a group of general formula V:

-CH (OH) -CH ₂ -CO-CH ₂ -CCOR where R represents an optionally substituted alkyl group containing up to 6 carbon atoms. The reduction can be achieved by means of sodium borohydride, preferably in a lower alkanol, e.g. ex. methanol, and preferably below room temperature, e.g. ex. at 0 ⁹ C or near.

According to another feature of the invention, compounds I where R4 represents a group of general formula II where R represents a hydrogen atom (R, R, R, X and Y are defined as above), or their salts, are prepared from the corresponding compounds where R ^ represents an optionally substituted alkyl group containing up to 6 carbon atoms, by hydrolysis by known methods, for example by reaction with an aqueous solution of the corresponding base, e.g. ex. an alkali metal hydroxide, to form the salt, e.g. ex. an alkali metal salt, optionally followed by acidification, e.g. ex. by treatment with acetic acid, to form the corresponding carboxylic acid.

According to another feature of the invention, compounds of formula I where R4 represents a group of formula II, where Y represents a carbonyl group and R4 represents an optionally substituted alkyl group, containing up to 6 carbon atoms, R being , R, R and X defined as above, are prepared by oxidation of the corresponding compounds where Y represents a hydroxymethylene group. The oxidation can be carried out by reaction with activated manganese dioxide, preferably at or near room temperature.

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According to another characteristic of the invention, those with 2 posts of formula I where X represents an ethylene group, R represents a group of formula II and R ³ represents an optionally substituted alkyl group containing up to 6 carbon atoms, Y being , R, R and R defined as above, are prepared from the corresponding compounds where X represents a vinylene group, by catalytic hydrogenation. Suitable catalysts are those containing palladium, e.g. palladium on charcoal or calcium carbonate, or mixtures thereof.

According to another characteristic of the invention, those with stations of formula I, where R represents a lactone ring of formula III, with R ³ , R, R ⁴ and X defined as above, are prepared by cyclization of the corresponding compounds where 3

R represents a group of formula II, where Y represents a hydroxymethylene group and R represents a hydrogen atom. Sometimes cyclization occurs spontaneously, but sometimes it is preferable to warm or warm the starting material. The heating is conveniently carried out in a solvent, such as toluene, at temperatures up to the boiling point. Optionally the reaction is carried out in the presence of traces of an acid, e.g. ex. glacial acetic acid.

Pharmaceutically acceptable salts can be prepared from parent compounds of formula I, for example, by reacting compounds of formula I (where R represents a group of formula II where R ³ represents a hydrogen atom) with the base appropriate, p. ex. an alkali metal hydroxide or carbonate, an alkaline earth metal oxide, ammonia or an amine, in a suitable solvent which is preferably water in the case of the preparation of alkali metal salts, alkaline — having roses, and water or isopropanol in the case of amine salts.

In addition to being useful in themselves as pharmaceutical compounds, the salts of the compounds of formula I where R represents a group of formula II where R represents a hydrogen atom, are useful for purifying the parent acids of formula I, p . by exploring the solubility differences between salts and parent acids in water and organic solvents.

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-15cos, by techniques well known to those skilled in the art. The acids of the formula I parents can be regenerated from their salts by methods already known, e.g. eg by treatment with a mineral acid, e.g. diluted hydrochloric acid, or with an organic acid, e.g. acetic acid.

As those skilled in the art can easily appreciate, the compounds of formula I, including their isomers mentioned above, can be separated by application or adaptation of known methods. For example, diastereoisomeric forms can be separated by chromatography using selective adsorption, from the solution or from the vapor phase on suitable adsorbents, and the enantiomeric forms of compounds of formula I where R represents a group of formula.

II where R represents a hydrogen atom, can be separated by the formation of salts, with an optically active base, followed by separation of the obtained pair of diastereoisomers, by, for example, fractional crystallization in a suitable solvent system, followed by separate regeneration of the enantiomeric acids.

The compounds of the formula shown in Figure IV can be prepared by applying or adapting known methods, e.g. eg by the methods illustrated in the following Reference examples.

For example, compounds of formula IV where X represents

2 4 7 - contains an ethylene group and R, R, R and R are defined as above, they can be prepared by catalytic reduction of the corresponding compounds in which X represents a vinylene group, under conditions similar to those previously described to prepare compounds of formula I where X represented an ethyl group in, by catalytic reduction.

X 2 4 * 7

The compounds of formula IV where R, R, r ', r' and X are defined as above, can be prepared from compounds of general formula VI, indicated at the end of this specification.

4 ^- cation, where R, R, R and X are defined as above, by reaction with a di-anion of a compound of the general formula ch ₃ coch ₂ coor

VZI

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-168 where R is defined as above, obtained in situ by treating 2 equivalents of a strong base, p. ex. sodium and / or butyllithium hydride, in a suitable solvent, such as tetrahydrofuran, between -50 ^and C and 0 ² C.

4

The compounds of formula VI, where R, R, R and X are from.

as defined above, can be prepared by oxidation of compounds of general formula VIII, indicated at the end of this specification, where R, R, R and X are as defined above under conditions similar to those previously described for the preparation of compounds of formula I where Y represents a carbonyl group, by oxidation.

4

The compounds of formula VIII where R, R, R and X are as defined above, can be prepared by reducing the compounds of general formula IX, indicated at the end of this specification, where R, R, R and X are defined as previously and R represents an alkyl group having 1 to 4 carbon atoms, for example, by means of diisobutylaluminum hydride, in a suitable solvent such as tetrahydrofuran, between -30 ⁹ C and +30 ^and C.

The compounds of formula IX where X represents a 12 4 9 vinylene group eR, R, R and R are as defined above, can be prepared from the compounds of formula X, indicated 12 4 at the end of this specification, where R, R and R they are as behind finids, by a Wittig reaction or a variant thereof, for example by reaction with the anion of a trialkyl phosphonoacetate obtained in situ by treatment with a strong base, e.g. sodium hydride), in a suitable solvent such as tetrahydrofuran, between -20 ^and C and 50 ^and C.

The compounds of formula IX where X represents a 12 4 9 ethylene group eR, R, R eR are as defined above, can be prepared by catalytic reduction of the corresponding compounds in which X represents a vinylene group, under conditions similar to those described above to prepare the compounds of formula I in which X represents an ethylene group, by catalytic reduction.

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-17f 2 4

The compounds of formula X in which R, R and R are as defined above, can be repaired from a compound of general formula XI, indicated at the end of this specification, where r \ R ² and R ⁴ are as defined above and R ^3-0 represents an alkyl group of 1 to 4 carbon atoms, through a series of reactions similar to those previously described to prepare compounds of formula VIII from compounds of formula IX.

The compounds of formula XI, where r \ R ² , R ⁴ and R ⁴ ° are as defined above, can be prepared from compounds of general formula XII, indicated at the end of this specification, 1 where R and R are as defined above, by reaction with a compound of general formula XIII:

r ² c = co ^{10 10} XIII where R ² and R ² are as defined above, in a suitable solvent for example acetonitrile or 1,3-dimethylimidazolin-2-one, at 10-100 ° C.

The compounds of formula XII, where R ^3- and R ⁴ are as defined above, can be prepared from a compound of general formula XIV, indicated at the end of this specification, ori of R and R are as defined above, by reaction with a mixture of acetic acid and fluoroboric acid at 3O-8O ⁹ C.

The compounds of formula XIV can be prepared by applying or adapting known methods for example, by the methods described by Podp & Soto, J. Chem. Soc. (1963), 1760.

Alternatively, compounds of formula XI, where R ¹ , R ² , R ^{4 and} r! ° are as defined above, can be prepared by acid-catalyzed hydrolysis and cyclization of an acetal of general formula XV, indicated at the end of this specification, onR ⁴ and R 1 are as defined above and R 4 represents an alkyl group having 1 to 4 carbon atoms, in a strong acid, for example a mixture of concentrated sulfuric acid and glacial acetic acid, at O-5 O 2 C. Alternatively, this reaction can be carried out step by step using the aldehyde corresponding to acetal.

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-18 Compounds of formula XV, where R ¹ , R ² , R ⁴ , R ¹ ^ e are as defined above, can be prepared from compounds of general formula XVI, indicated at the end of this specification, where R ¹ , R ² , R ⁴ θ R ¹⁰ are as defined above, by reaction with a compound of general formula XVIIa:

zlCH ₂ CH (ÓRTL) ₂ XVIIa where -R ¹¹ is as defined above and Z ^{1 represents} a halogen atom, in the presence of a suitable base, p. ex. sodium hydroxide and, optionally, in the presence of a phase transfer catalyst, e.g. ex. tris / "2- (2-methoxyethoxy) ethyl_Z7 amine, in a suitable solvent such as dimethylformamide, at 0—50-C.

Alternatively, compounds of formula XV, where R ¹ , R ² , R ⁴ , ° ⁰ and R ¹¹ are as defined above, can be prepared from compounds of general formula XVIII, indicated at the end of this specification, where R ¹ , r ² , r ⁴ and R ⁴ ° are as defined above, by reaction with a compound of general formula XVIlb:

N ^ C ^ CHfOR ¹¹ ) ₂ XVIlb where R ¹¹ is as defined above, optionally in the presence of acetic acid and at 5O-17O ⁹ C.

Compounds of formula XVIII, where R ¹ , r ² , R ⁴ and R ^{1 <3} are as defined above, can be prepared from compounds of general formula XIX

R ² CH = C (COR ¹ ) COOR ¹⁰ XIX where R ¹ , R ² and Ρ ¹ θ are as defined above, by reaction with a compound of general formula XX, indicated at the end of this specification, where R is as above defined, in the presence of an organic base, p. ex. triethylamine, and a suitable catalyst, e.g. ex. 3,4-dimethyl-5— (2-hydroxyethyl) thiazolium iodide, in a suitable solvent, e.g. ex. ethanol, and 4O-8O2C.

Compounds of formula XIX, where R ^, R ² and R ^{1 <3} are as defined above, can be prepared from compounds of general formula XXI:

r ¹ coch ₂ coor ¹⁰

XXI

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-19where r! and R ^ ° are as defined above, by condensation with a compound of general formula XXII:

R ² CH0 XXII where R is as defined above, in the presence of a suitable catalyst, e.g. ex. piperidinium acetate, and a suitable solvent, e.g. ex. toluene, preferably under reflux, with azeotropic removal of water.

Alternatively, compounds of formula XV where R ^,

R ² , R ⁴ , R · ¹⁰ and R ¹ ^ are as defined above, they can be prepared from a compound of formula XXIII, indicated at the end of this specification, where R, R and R are as defined above 2 of , by reaction with a compound of formula XIII (where R and R3 are as defined above) in acetic anhydride and in the presence of a base, e.g. ex. triethylamine, and O-5O ⁹ C.

The compounds of formula XXIII where r \ R ⁴ and as indicated above, can be prepared by hydrolysis of a compound of general formula XXIV, indicated at the end of this specification, where R ⁴ , R ⁴ and r H are as indicated above and R ^3-2 represents an alkyl group of 1 to 4 carbon atoms, by hydrolysis of esters, e.g. ex. reaction with sodium hydroxide in aqueous methanol, followed by acidification, p _and Ex. through hydrochloric acid.

The compounds of formula XXIV, where R ² , R ⁴ , R ^2-2- and R ^2-2 are as defined above, can be prepared from compounds of general formula XXV, indicated at the end of this specification, where R ⁴ , R ^2- ^ and R ^{2 2} are as defined above, by reaction with a compound of general formula XXVI:

R ^ -COZ ² XXVI

2 where R is as defined above and Z represents a halo atom in a suitable solvent, e.g. ex. dichloromethane, and preferably in the presence of a base, e.g. ex. triethylamine.

Compounds of formula XXV, where R ⁴ , R ^ and R ^ ² are as defined above, can be prepared from compounds of general formula XXVII, indicated at the end of this specification,

12 3 where R and R are as defined above and Z represents an atom

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-20m halogen, by reaction with a compound of formula XVIIb where rH is as defined above, in a suitable solvent, e.g. ex. acetonitrile, in the presence of a base, e.g. ex »triethylamine, at 10-50 ° C.

Alternatively, the compounds of formula XV, on of R ¹ , R ⁴ , R ¹⁰ (

2 - and R are as defined above and E represents an optionally substituted aryl or heterocyclyl, can be prepared from compounds of general formula XXVIII, 4 indicated at the end of this specification, where R is as defined above 13 and R represents a heterocyclyl group or optionally substituted aryl and within the definition of R, by reaction with a compound of formula XVIIb (where it is as defined above! and with a compound of general formula XXIX:

R ^ COCH ^ CCOR

XXIX where R and R are as indicated above, in the presence of a Lewis catalyst, p. ex. zinc chloride, in a suitable solvent, e.g. ex. ethanol, 40-80-C. Due to the possibility of producing mixtures of compounds, this process is more suitable for the preparation of compounds of formula XV where the symbols R all represent hydrogen, that is, the compound of formula XXVIII is preferably benzoin.

The intermediate compounds of general formula VII, XIII, XVI, XVIIa, XVIIb, XX, XXI, XXII, XXVI, XXVII, XXVIII and XXIX, where the various symbols are as defined above, are already known or can be prepared by application or adaptation of already known processes.

The following Examples illustrate the preparation of compounds according to the present invention, and the Reference Examples illustrate the preparation of intermediate compounds.

In the presentation of the naked clear magnetic resonance (NMR) spectrum, DMSO-dg stands for deuterium dimethylsulfoxide, s, d, t, q, in singlet, doublet, triplet, quartet and multiplet respectively, “dd means doublet of doublets, dt stands for doublet of triplets, b stands for broad and the positions

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-21 signal directions are indicated in parts per million in relation to the tetramethylsilane signal.

EXAMPLE 1

Compound A

A stirred solution of methyl (E_) - 5-hydroxy-7 - (3-isopropyl-1-phenylpyrrole / ^- 2,1-y-7 is oquinolin-2-yl) -3-oxo-hept-6-enoate (650 mg, prepared as described in Reference Example 1) in methanol (20 ml) ^and was cooled to 0 C and treated with sodium borohydride (30 mg). The mixture was stirred at 0 ^and C for 3 minutes and then poured into a mixture of ice and water (50 ml). The resulting mixture was extracted with diethyl ether (3x40 ml), the ether extracts were added, washed with brine, dried over magnesium sulfate and evaporated and the residue was subjected to chromatography, flash gel on gel silica using a mixture of dichloromethane and methanol (19: 1 v / v) as eluent, obtaining (E) -3,5-dihydroxy-7- (3 —isopropyl-1-phenylpyrrole / 72, Methyl 1-a_7isoquinolin-2-yl) hept-6-enoate (450 mg) as a light yellow solid substance, mp 146-15O ^and C. ( ⁱⁿ

CDC1 ₃ and D ₂ 0): 1.50 (6H, d, J = 7Hz), 1.6-1.8 (2H, m), 2.4-2.5 (2H, m), 3.65 (1H, septet, J = 7Hz), 3.74 (3H, two s), 4.0 -

-4.1 (1H, m), 4.25-4.4 (1H, m), 5.25 and 5.32 (1H, two dd,

J = 16 and 6 Hz), 6.61 and 6.65 (1H, two d, J = 16 Hz), 6.70 (1H, d, J = 8Hz), 7.0-7.56 (9H, m), and 7.84 (1H, d, J = 8Hz) ^ 7.

spectrum of R.M.N. indicated that the product was a 3: 2 mixture of the erythro and threo diastereoisomers.

EXAMPLE 2

Compound B

A solution of a 3: 2 mixture of diastereoisomers (E) -3,5-di — hydroxy — 7— (3 — isopropyl — l — phenylpyrrole / 72, l-a_7isoquinolin — 2 — il) hept— Methyl 6-enoate (300 mg; prepared as described in Example 1) and sodium hydroxide

073

Ref: PAT / BQ / CH / 644 / E tf

Case 1111 / PT

-2 2 (26 mg) in a mixture of water (1 ml) and methanol <10 ml), was stirred, under an argon atmosphere, at room temperature for 2.5 hours. The solution was then evaporated in vacuo and there. the residue was removed with diethyl ether <5x20 ml). The residue was dried by the following method: dissolved in methanol (<20 ml), and the methanol was evaporated in vacuo and this operation was repeated 2 more times. The (E.) - 3,5-di — h idr oxy— 7 - <3 - is opr opyl-1— phenyl Pyrrole / f ^- 2, 1 / 7is oquinol in-2-yl) hept- Sodium 6-enoate (260 mg) in suede solid, mp 213—2179C <with decomposition). <~ NMR (in DMSO-d ^ and D ₂ 0): 1.1-1.3 (2H, m), 1.46 (6H, d, J = 7Hz), 1.75-2.1 (2H , m), 3.53-3.79 (2H, m), 4.02—4.15 <1H, m), 5.24 and 5.27 (IH, two dd, J = 16 and 6 Hz) , 6.45 (IH, dd, J = 16 and 1 Hz), 6.82 (IH, d, J = 8 Hz), 7.0-7.61 (9H, m), and 8.1 (IH , d, J = 8 Hz). The NMR spectrum indicated that the product was a 2: 1 mixture of erythro- and threo-d iastere omer.

EXAMPLE 3

Compound C

Proceeding in a manner similar to that previously described. in Example 1 but replacing (E) —5 — hydroxy — 7- (3 — isopro pi1-1-phenylpyrrole // 2, la / 7isoquinolin-2-yl) -3-oxo-hept — methyl 6enoate, used with starting material, by the appropriate amount of (E) —5-hydroxy-7 - (3-isopropyl-1-phenylpyrrz / 2,1-α-7isoquinolin-2-i1) -3 — oxo-hept — 6-enoate Ethyl, prepared as described in Reference Example 2, prepared a mixture of the erythro and threo diastereoisomers of (E) -3,5-dihydro oxy-7- (3-is opr opil-1 - feni Ipirr olo / 7 “2, la / 7isoquinolin-2 — yl) hept — ethyl 6-enoate, in the form of yellow gum.

EXAMPLE 4

Compound D

A mixture of (E.) - 3,5-di-h idr ox i-7- (3 —is opr opi 1-1-f e -

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

nilpirrolo_ /-2, l-aJ7i Q ^u i ^s morpholin-2-yl ⁿ⁾ hept-6-enoate (157 mg; prepared as described in Example 3) dioxy of activated manganese (1.74g ) and diethyl ether (25 ml) was stirred at room temperature in an argon atmosphere for 2 hours. The suspension was filtered, the solids were extracted with diethyl ether (3x15 ml). The filtrate was added to the extracts and evaporated in vacuo, yielding (E) -3-hydroxy-7- (3-is opropi1-1-phenylpyrrole / 72, 1 ^ 7is oquinolin-2-yl) -5-oxo-hept-6-enoate (80 mg), in the form of orange gum. /fR.NN (in CDCl ^): 1.26 (3H, t, J = 7Hz), 1.55 (6H, d, J = 7Hz), 2.48 (2H, d, J = 7 Hz), 2.55 (2H, d, J = 7 Hz), 3.76 (IH, septet, J = 7 Hz), 4.19 (2H, q, J = 7 Hz),

4.41 (IH, quintet, J = 7 Hz), 5.71 (IH, d, J = 16 Hz),

6.73 (IH, d, J = 8Hz), 7.01-7.59 (9H, m), 7.03 (IH, d, j =

Hz), 7.04 (IH, d, J = 16 Hz); Mass spectrum (electron impact) m / e = 469_7 ·

EXAMPLE 5

With E

A mixture of sodium hydroxide (120 mg), water (2 ml), methanol (10 ml) and (E) —3-hydroxy-7- (3 —isopropyl-1-phenylpyrrole Z / 2, 1-a_Visoquinolin — 2 —Yl) -5-oxo-hept-6-enoate (230 mg; prepared as described in Example 4), was stirred under an argon atmosphere at room temperature for 5 hours. Water (10 ml) was added and the solution was acidified to pH 5 by treatment with glacial acetic acid. The milky solution was extracted with diethyl ether (4x50 ml) and the extracts together were dried over magnesium sulfate and evaporated, yielding (E) -3-hydroxy-7- (3-isopropyl-l-phenylpyrrole / 72) , l-aT7isoquinolin-2 — yl) -5 — oxo-hept-6-enoic, (80 mg), in the form of suede-colored foam, mp 95-100 ^and C. (Elemental analysis:

C 76.7; H, 6.57; N, 3.02%; Calculated; C, 76.2; H, 6.16; N,

3.2%. NMR (in CDC1 ₃ and D ₂ 0): 1.56 (6H, d, J = 7Hz), 2.54 (2H, d, J = 7Hz), 2.55 (2H, d, J = 7Hz), 3.76 (IH, septet J = 7Hz), 4.42 (IH, quintet, J = 7Hz), 5.68 (lH, d, J = 16Hz), 6.75 (IH, d, J = 8Hz) , 7.03-7.57 (9H, m), 7.84 (IH, d.

073

Ref: PAT / BQ / CH / 644 / Ε

Case 1111 / PT

-24J = 8Hz), 7.86 (1H, d, J = 16 Hz) J7.

EXAMPLE 6

Compound F

Sodium borohydride (38 mg) was added to a stirred solution of 5-hydroxy-7- (3-isopropyl1-1-phenylpyrrole / 72,1-a isoquinolin-2-yl) -3-oxo-heptanoate ethyl (760 mg; prepared as described in Reference Example 3), in methanol (20 ml) at 0 ^and C, under an argon atmosphere. The mixture was stirred at 30 minutes and a solution of sodium hydroxide (320 mg) in water (8 ml) was added and the mixture was stirred for 1 hour. The mixture was diluted with water (20 ml) and acidified with glacial acetic acid. The resulting milky mixture was extracted with diethyl ether (3x50 ml) and the extracts together were dried over magnesium sulfate and evaporated to give the acid. do 3,5-dihydroxy-7- (3-isopropyl-1-phenylpyrrole / 72,1-isoisoquinolin-2-yl) heptanoic, in the form of yellow gum (730 mg).

EXAMPLE 7

Compound G

A solution of 3,5-dihydroxy — 7- (3 — isopropyl — 1-phenylpyrrole / 2 ~ 2, l-a_7isoquinolin — 2 —yl) heptanoic acid (712 mg; prepared as described in Example 6) in toluene (100 ml), containing glacial acetic acid (5 drops), was heated under stirring at 100 ° C for 4 hours. The solution was then evaporated in vacuo to obtain an orange gum, which was subjected to flash chromatography on silica gel, using a mixture of dichloromethane and methanol (19: 1 v / v) as eluent, obtaining a mixture 1: 2 of the cis and trans isomers of the lactone ring of 4-hydrox i-6-ΖΓ2- (3-isopropyl-1-phenylpyrrole // 2,1-a_Z7isoquinolin-2-yl) et il_Z / -3,4, 5.6 - (tetrahydrochloride) -2H-pyran-2-one (310 mg) as a yellow foam, mp 99-1022 ° C. ZZ ~ Electronic analysis: C, 78.8; H, 7.0; N, 3.0 ° /; Calculated: C, 78.7; H, 6.84; N,

-2568 073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

3.28%; NMR (in CDCl ₃ and D ₂ 0): 1.50 (6H, d, J = 7 Hz), 1.5—2.2 (4H, m), 2.34-2.88 (4H, m) , 3.57 (IH, d, septet,

J = 2 Hz, 7Hz), 3.9-4.16, 4.2-4.32, 4.44—4.6 (2H, 3 xm), 6.69 (IH, d, J = 8Hz) , 7.0-7.55 (9H, m), 7.85 (IH, d, J = = 8 Hz); Mass spectrum (electron impact) m / e = = 427/7.

EXAMPLE 8

Compound H

Proceeding in a manner similar to that previously described in Example 1, but replacing (E) -5-hydroxy-7- (3-isopropyl-1-phenylpyrrole // 2, la / 7isoquinolin-2-yl) -3-oxo-hept Methyl -6-enoate, used as a starting material, by an appropriate amount of (Ξ) -5-hydroxy-7- (3-methyl-1-phenyl pyrrole // 2, 1 / 7is oquinolin-2-yl ) -3 -oxo-hept-6-enoate, prepared as described in Reference Example 4, (E) —3,5-dihydroxy-7- (3-methyl-1- phenylpyrr0I0 / 72,

Ethyl 1-a / 7isoquinolin — 2-yl) hept-6-enoate, in the form of a gum. /AshR.M.N. (in CDCl ^): 1.20-1.34 (3H, t, J = 7Hz), 1.40-1.80 (2H, m), 2.46 (2H, m), 2.56 (3H , s), 4.10-4.30 (3H, m), 4.30-4.46 (IH, m), 5.46 and 5.50 (IH, dd, J = 7 and 16 Hz), 5.51 and 6.54 (1H, d, J = 16 Hz), 6.76 (IH, d, J = 8 Hz), 7.08 (IH, dt, J = 2 and 8 Hz), 7, 14-7.28 (IH, m), 7.30-7.60 (7H, m), 7.62 (IH, d, J = 8Hz) //.

EXAMPLE 9

Compound I

Proceeding in a similar manner to that previously described in Example 2, but replacing (E) -3,5-dihydroxy-7- (3-isopropyl-1-phenylpyrrol // 2, la / 7is oquinolin-2 —il) ethyl hept-6-enoate, used as a starting material, by an appropriate amount of (E) -3,5-dihydroxy-7- (3-methyl-1-phenylpyrrole / 72, l-a_7isoquinolin-2- il) ethyl hept-6-enoate, prepared as described in Example 8, (E) —3,5-dihydroxy—

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

-26-7 - (3 —me t i 1—1-phenylpyrrole / T 2, l-a_ / 7isoquinolin-2-yl) -hept-6-enoate, in the form of brown powder. R.M.N. (in DMSO-dg): 1.10-1.60 (2H, m), 1.70-2.10 (2H, m), 2.55 (3H, s), 3.10-3.85 ( IH, m), 4.00-4.20 (IH, m), 4.60-4.95 (IH, b), 5.43 and 5.48 flH, dd, J = 6 and 16 Hz), 6.35 (IH, d, J = 16 Hz), 6.91 (IH, d, J = 7Hz), 7.00-7.70 C9H, m), 7.97 (IH, d, J = 7Hz ) J7.

EXAMPLE 10

Compound J

Proceeding in a manner similar to that previously described in Example 1, but replacing (E) —5-hydroxy — 7- (3-isopropyl -1-phenylpyrrole // 2, 1-a_ / 7is oquinolin-2-i 1) -3 methyl oxo-hept-6-enoate, used as a starting material, by an appropriate amount of (E) -5-hydroxy — 7— (3-ethyl-1— (4-fluorophenyl) pyrrole / ~ 2, la ^ 7isoquinolin) -3-oxo-hept-6-enoate, prepared as described in Reference Example 5, (E) -3,5-dihydroxy-7- (3-ethyl- ethyl 1- (4-fluorophenyl) pyrrole // 2,1-α / isoquinolin-2-yl) hept — 6-enoate. // NMR (in CDC1 ₃ ): 1.20-1.39 (6H, m), 1.50-1.80 (2H, m), 2.48 (2H, m), 4.19 (2H, q, J = 7Hz), 4.30-4.50 (lH, m), 5.46 and 5.50 (IH, dd, J = 6 and 16Hz), 6.48 and 6.50 (IH, dd , J = 2 and 16Hz), 6.75 (IH, d, J = 7Hz), 7.00-7.44 (7H, m), 7.48 (IH, d, J = 7Hz), 7.67 (IH, d, J = 7Hz) / 7.

EXAMPLE 11

Compound K

Proceeding in a manner similar to that previously described in Example 2, but replacing ο (Ξ) -3,5-dihydroxy-7- (3-isopropyl-1-phenylpyrroleZ ”2, 1-a7isoquinolin-2-yl) hept-6 -methyleneate, used as a starting material, by an appropriate amount of (E) -3,5-dihydroxy-7- (3-ethyl-1- (4-fluorophenyl) pyrrole / “2, la / 7isoquinolin -2-yl) ethyl hept — 6-enoate, prepared as in Example 10, (E _) - 3,5 — di-hydroxy - _7— (3-ethyl-1- (4-fluorophenyl) pyrrole was prepared // 2, la / 7isoquinolin-2-yl).

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

-27tf t / A 'Ay hept-6-enoate sodium, in the form of a brown powder, m.p. 217-2212C. /AshR.M.N. (in DMSO-dg): 1.10-1.60 (4H, m), 1.70-2.20 (2H, m), 3.05 (2H, q, J = 7Hz), 3.56- 3.84 f1H, m), 4.01-4.09 C1H, m), 4.60-5.00 (1H, bm), 5.42 and 5.45 (1H, dd, J = 6 and 16 Hz), 6.31 f1H, d, J = 16Hz), 6.90 (1H, d, J = 7Hz), 7.04-7.56 (7H, m), 7.62 (1H, d, J = '6Hz), 8.03 (1H, d, J = 7Hz) J7.

EXAMPLE 12

Compound L

Proceeding in a manner similar to that described in Example 1 but replacing (E) -5 — hydroxy-7-f3-isopropyl-1-phenylpyrr0O0 / 72, 1-aJ7isoquinolin-2-i1) —3-oxo — hept-6-enoate methyl, used as starting material, by an appropriate amount of E1) -5-hydroxy — 7- (1-isopro pil-3- (4-fluorophenyl) pyrol / S2, l-a_77isoquinolin-2-yl) -3 - ethyl oxo-hept-6-enoate, prepared as in Reference Example 6, (E) —3,5 — di— -hydroxy-7 - (1-is opropi1-3 - (4 -fluorophenyl) pyrrole / ^- 2,1-l-7'o-quinolin-2-yl) ethyl hept-6-enoate, in the form of colorless viscous oil. zS ~ ^R 'MN (in CDCl ^ and D ^ O); 1.27 Γ3Η, t, J = 7 Hz), 1.4-1.7 (8H, m), 2.39-2.47 (2H, m), 4.0 (1H, septet J = 7Hz) , 4.05-4.15 (3H, m), 4.34-4.46 (1H, m), 5.3 and 5.37 (1H, two dd, J = 6 and 16Hz), 6.55 (1H, d, J = 8Hz), 6.82 and 6.84 <1H, two dd, J = 1 and 16Hz), 7.1-7.52 (8H, m), 8.25 (1H, d , J = 8Hz). The NMR eSDectro indicated that the product was a 3: 2 mixture of the erythro and threo diastereoisomers.

EXAMPLE 13

Compound M

Proceeding in a manner analogous to that described in Example 2, but replacing the (E) -3,5-di-hydroxy-7- (3-isopropyl-1 — phenylpyrrole / T * 2, l-a_Z7isoquinolin-2-yl) hept— Methyl 6-enoate, used as a starting material, by an appropriate amount of (E) -3,5-dihydroxy — 7- (1-isopropyl1-3- (4-fluorophenyl) pyrrole // 2, 1 -a_7isoquinolin — 2 —il) hept — ethyl 6-enoate, prepared as

073

Re f: PAT, / BQ / CH / 644 / E

Case 1111 / PT

-28 In Example 14, <E) -3,5-dihydroxy-7- (1-isopropyl-3-f4-fluorophenyl) pyrol was prepared / ^- 2,1-o-7is oquinolin-2-ill sodium hept-6-sodium, in the form of a light yellow solid, mp 225 ° c (with decomposition) / ^ Elemental analysis: C, 67.4;

H, 5.7; N, 2.7; H ₂ 0, 3.6%; Calculated: C, 67.1; H, 5.8; N, 2.8; H „0, 3.6%; NMR (in DKSO-d. And D _n 0): 1.05-1.4 (2H, m), 1.47

Ζ Ό Z f6H, d, J = 7Hz), 1.7-2.05 (2H, m), 3.5-3.8 (lH, m), 3.97 (IH, septet, J = 7Hz) , 4.0-4.19 (IH, m), 5.28 and 5.31 (IH, two dd, J = 6 and 16Hz), 6.63 flH, d, J = 16Hz), 6.72 ( 1H, d, J = 8Hz), 7.27-7.63 <8H, m), 8.21 (IH, d, J = 8Hz). The R.M.N. indicated that the product was a 3: 2 mixture of erythro and threo diastereoisomers.

EXAMPLE 14

Compounds N, NA and NB

Proceeding analogously to that described in Example 1 but replacing <E) -5-hydroxy-7- (3-isopropyl-1-phenylpyrrole ^ 2, 1-αJ7isoquinolin-2-yl) -3-oxo-hept-6- methyl enoate, used as the starting material, by an appropriate amount of (E) -5 -h idr ox i-7 - (3 - isopile-1- (4-fluorophenyl) pyrrole-2 ~, 1-a_ “7is c> quinolin-2-yl) -3-oxo-hept-6-enoate, prepared as in Reference Example 7, (E) -3,5-dihydroxy— 7- (3-is opropi1-1- (4-fluoropheni1) pyrrole / ^- 2, 1-y / 7is oquinolin-2 — i1) ethyl hept-6-enoate, in the form of yellow gum.

A portion of this substance (1.0 g) was subjected to HPLC on a column of silica gel, using a mixture of hexane, ethyl acetate and methanol (9.5: 0.5 v / v) as eluent, obtaining erythro- (E) -3,5-dihydroxy-7- (3-isopropyl-1- (4-fluorophenyl) pyrrole / 2, 1-7is oquinolin-2-yl) hept-6-enoate ethyl (0.34 g) as a light yellow gum. /? NMR (in CDC1 ₃ and D ₂ 0): 1.28 (3H, t, J = 7Hz), 1.32-1.68 (8H, m), 2.42-2.48 <2H, m ), 3.64 (IH, septet, J = 7 Hz), 4.08 -4.25 <3H, m), 4.30-4.42 flH, bm), 5.25 (IH, dd, J = 6 and 16Hz), 6.59 (IH, dd, J = 1 and 16Hz), 6.69 (IH, d, J = 8Hz), 70.1-7.52 (8H, m), 7.82 ( IH, d, J = 8Hz) J7, and treo- (E) -3,5-dihydroxy-7- (3-isopropyl1-1- (4-fluorophenyl) pyrrolo_ / 2, l-a_7isoquinolin-2-yl ) ethyl hept-6-enoate (0.28 g),

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

-29 in the form of light yellow gum. /7&·Μ.Ν. (in CDCl ^ and D 0): 1.28 (3H, t, J = 7Hz), 1.35-1.75 (8H, m), 2.39-2.46 (2H, m), 3, 63 (IH, septet, J = 7Hz), 4.06-4.25 (3H, m), 4.32-4.44 (IH, bm), 5.32 (IH, dd, J = 6 and 16 Hz), 6.39 (IH, dd, J = 1 and 16Hz), 6.69 flH, d, J = 8Hz), 7.01-7.51 (8H, m), 7.82 (IH, d , J = 8Hz) J7.

EXAMPLE 15

Compounds 0, OA and OB

Proceeding in a manner analogous to that described in Example 2, but replacing (E) -3,5-dihydroxy-7- (3-isopropyl-1-phenylpyrr0O0 / 72, 1-α7isoquinolin-2-yl) hept-6- methyl enoate, used as the starting material, by an appropriate amount of (E) -3,5-dihydroxy-7 - (3-is opropi1-1- (4-fluoropheni1) pyrr0O0 / 72, 1-asoquinolin -2-yl) ethyl hept-6-enoate, prepared as in Example 14, (E) -3,5-dihydroxy-7- (3-isopropyl-1- (4-fluoropheni 1) was prepared ) pyrrole / Z 2,1-a J7isoquinolin-2 - yl) sodium hept-6-enoate, in a solid suede color, mp 20.7 210 ^g C (with decomposition). Z ~ Elemental analysis: C, 66.3; H,

6.3; N, 2.5; HO, 4.5%; Calculated: C, 65.9; H, 5.93; N, 2.7; H ₂ 0, 5.3%; NMR (in DMSO-dg and D ₂ 0): 1.1-1.3 (2H, m), 1.46 (6H, d, J = 6Hz), 1.72-2.08 (2H, m) , 3.5-3.8 (2H, m), 4.0—4.15 (IH, m), 5.19 and 5.25 (IH, two dd, J = 6 and 16Hz), 6.44 (IH, dd, J = 1 and 16Hz), 6.85 (IH, d, J = 8Hz), 7.05-7.63 (8H, m), 8.13 (IH, d, J = 8Hz) . The NMR spectrum indicated that the product was a 3: 2 mixture of the erythro and threo diastereoisomers.

In a similar way, but using the separate erythro and threo diastereoisomers, prepared as in Example 14, erythro- (E) -3,5-dihydroxy-7- (3-isopropyl-1- (4- fluorophenyl) pyrr010 / C2, l-a7is oquinolin-2-yl) sodium hept-6-enoate, in a solid suede color, mp 215-22O ^and C (with decomposition). Z7R.MN (in DMSO-dg and D ₂ 0): 1.04-1.3 (2H, m), 1.45 (6H, d, J = 7Hz), 1.74-2.10 (2H, m), 3.54-3.78 (2H, m) 4.01-4.16 (IH, m), 5.2 (IH, dd, J = 6 and 16Hz), 6.44 (lH, di ,

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT%

-30J = 8Hz), 7.04-7.61 (8H, m), 8.12 tre o- (E) -3.5-d i-hydrox i-7- (3-is ODroj = 16Hz), 6, 85 (1H, d, (1H, d, J = 8Hz) / 7; and pi1-1- (4-fluorophenyl) pyrrole / 72, la / 7isoquinolin-2-yl) hept — 6-sodium enoate, under solid suede color, mp 218-223 ⁹ C (with decomposition). // NMR (in DMSO-dg and D ^ O): 1.04-1.3 (2H, m), 1.45 (6H, d, J = 7Hz), 1.72-2.06 (2H, m), 3.54-3.82 (2H, m), 4.02-4.17 (1H, m), 5.25 (1H, dd, J = 6 and 16Hz), 6.45 (1H, dd, J = 16Hz), 6.84 (1H, d, J = 8Hz), 7.01-7.64 (8H, m), 8.12 (1H, d, J = 8Hz) 27.

EXAMPLE 16

Compound P

Proceeding in a similar manner to that described in Example 4 but replacing (E.) - 3,5-d ih idr oxy-7- (3-is opr opil-lfeni 1pyrrole // 2, l-a_ / 7is oquinolin-2 -yl) ethyl hept-6-enoat, used as starting material, by the appropriate amount of (E) -3,5-dihydroxy-7- (3-is opropyl-1- (4-fluorophenyl) pyrrole // ethyl 2, la / 7isoquinolin-2-yl) hept-6-enoate, prepared as in Example 14, (E) -3-hydroxy — 7- (3-isopropyl 1-1 - (4 —Fluor of eni 1) pyrroloZ / 2, la / 7isoquinolin-2-yl) -5-oxohept-6-enoate in the form of amber oil. //R.M.N.

(in CDC1 ₃ ): 1.28 (3H, t, J = 7Hz), 1.54 (6H, d, J = 8Hz),

2.55 (4H, m), 3.62 (1H, d, J = 3Hz), 3.77 (1H, septet,

J = 8Hz), 4.18 (2H, q, J = 7Hz), 4.45 (lH, m), 5.73 (lH, d,

J = 16Hz), 6.76 (1H, d, J = 8Hz), 7.16-7.54 (8H, m), 7.777.90 (2H, m) _7.

EXAMPLE 17

Compound Q

Proceeding analogously to Example 2 but replacing (E) -3,5-dihydroxy-7- (3-isopropyl-1-phenylpyrrole / 72,

1 — a_7isoquinolin — 2-yl) hept-6-enoate, used as a starting material, by an appropriate amount of (E) -3-hydroxy-7- (3-isopropyl-1- (4-fluor of enil ) pyrrole // ”2, l-y / 7isoquinolin-2-yl) 6 8 07 3

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

-3 1 -

Ζ

-5-oxo — ethyl hept-6-enoate, prepared as in Example 16, ο (Ξ) -3-hydroxy-7- (3-isopropyl-1- (4-fluorophenyl) pyrrole // 2, la / 7isoquinolin-2-yl) -5-oxo-hept-6-enoate sodium, in a golden brown solid form, mp 1402C (with composition). / “Elementary analysis: C, 67.4; H, 5.37; N, 2.73; F, 3.59; H ₂ 0 2.9%; Calculated: C, 67.33; H, 5.45; N, 2.80; F, 3.81; H ₂ 0, 3.6% / 7.

REFERENCE EXAMPLE 1 (a) An aqueous solution of fluoroboric acid (48% w / v; 33 ml) was added to a stirred solution of 1-cyano-2-isobutyl-1,2-dihydroisoquinoline (6 , 78 g, prepared according to the method described by FD Popp and A. Soto, J. Chem. Soc., 1963, 1760), in acetic acid (25 ml) at 60 ^and C. The solution was stirred for 15 minutes and cooled to 5 ° C. The solid part was collected, washed very well with diethyl ether and dried, yielding 1-amino-3-isopropyloxyzole / ~ 4,3-a Visoquinolinium tetrafluoroborate (8.55 g) under light yellow solid form, mp 181-1832C. / “Elementary analysis: C, 53.0; H,

4.78; N, 8.9%; Calculated; C, 53.5; H, 4.81; N, 8.9%; R.M.N. in CD ^ CN: 1.44 (6H, d, J = 7Hz), 3.68 (IH, septet, J = = 7Hz), 5.90 (2H, broad s), 7.27 (IH, d, J = 8Hz), 7.48-7.72 (4H, m), 7.92 (IH, d, J = 8Hz); Mass spectrum (rapid atomic bombardment) m / e »227/7.

(b) Ethyl phenylpropiolate (10.1 g; 0.058 mol) was added with stirring to a solution of 1-amino-3-isopropyloxazole tetrafluoroborate // 4,3- £ / 7isoquinoline (9.1 g) it in acetonitrile (90 ml) at 50 C. ^and the solution heated under reflux for 30 minutes and evaporated in vacuo to give an orange - brown viscous oil which was extracted with petroleum ether Hot te (p. b 60-802C) (4x100 ml). The petroleum extract was evaporated in a vacuum and the residue was subjected to flash chromatography on silica gel using a mixture of petroleum ether (p. Eb. 40-602C) and diethyl ether (19: 1 v) as eluent. / v) obtaining an oil which crystallized after standing and which was 3-isopropyl68 073

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Case 1111 / PT

-32-1-phenylpyrrole // 2, la./7 ethylisoquinoline -2- carboxylate (1.7 g 'in colorless solid form, mp 82-845 ° C. // NMR (in CDCl ₃ ): 0.88 (3H , t, J = 7Hz), 1.52 (6H, d, J = 7Hz), 4.01 (2H, q, J = 7Hz), 4.14 f 1H, septet, J = 7Hz), 6.75 flH, d, J = 8Hz), 7.00-7.50 (9H, m) and 7.85 (1H, d, J = 8Hz) _ / 7.

(c) A solution of ethyl 3-isopropyl-1-phenylpyrrole— / ~ 2,1-a / 7isoquinoline-2-carboxylate (6.25 g) in anhydrous diethyl ether (100 ml) was added to a stirred solution of hydre. aluminum and lithium (2.7 g) in diethyl ether (160 ml) at -2-C in an argon atmosphere. The mixture was stirred between -5 s and 0-C for 5 h and the reaction was quenched by the dropwise addition of ethyl acetate (50 ml), followed by dilute hydrochloric acid (in ml; 1 N) maintaining temperature below 10 ⁵ C. The organic phase was then separated. The aqueous phase was extracted with dichloromethane (2x150 ml), the organic solutions were added, washed with brine (300 ml), dried over magnesium sulfate and evaporated to 2-hydroxymethyl. -3-isopropyl-1-phenylpyrrole // 2,1-a / 7isoquinoline (l5) in a yellow, sticky solid form. // NMR (in DMSO-d_):

D

1.48 (6H, d, J = 7Hz), 3.65 (1H, septet, J = 7Hz), 4.3 (2H, d, J = 4Hz), 4.5 (1H, wide t, J = 4Hz), 6.85 (1H, d,

J = 8Hz), 7.0-7.7 (9H, m) and 8.1 (1H, d, J = 8Hz) Σ7.

(d) A mixture of 2-hydroxymethyl-3-isopropyl-1-phenylpyrrole // 2,1-a ^ // oquinoline (2.05 g), active manganese dioxide (22.56 g) and diethyl ether (120 ml) was stirred at room temperature, under an argon atmosphere, for 16 h. The suspension was filtered, the filtrate was evaporated and the resulting residue was subjected to flash chromatography on silica gel, using a mixture of petroleum ether (p. Eb. 40-60 ^and C) and diethyl ether (3) as eluent. : 1 v / v), obtaining 3-isopropyl-1-phenylpyrr0O1 // 2, 1 / 7isoquinoline-2-carboxaIdehyde (1.3 g) in solid yellow form, mp 134-136%. // NMR (in CDC1 ₃ ): 1.54 (6H, d, J = 7Hz), 4.30 (1H, septet, J = 7Hz), 6.82 (1H, d, J = = 8Hz), 7 , 06-7.54 (9H, m), 7.89 (1H, d, J = 8Hz) and 9.76 (1H, s). Mass spectrum (electron impact) m / e = 313/7.

8 07 3

Ref: PAT /BQ/CH./644.'E Case 1111 / PT

-3 3-

, - * '(e) A dispersion of sodium hydride in oil (80%; 12 mmol) was washed with hexane and then dried under an argon stream. Was suspended sodium hydride in tetrahydrofuran was co (20 ml) and cooled to -152C between ² and -9 are then joined C. drop by drop triethyl phosphonoacetate (2.7 g) to the suspension, under argon, and the mixture was stirred for 45 minutes. The mixture was then treated dropwise with a solution of

-is opropyl-1-phenylpyrrole / ^- 2, 1: 7is oquinoline-2-carboxy Idei. (2.5 g) in dry tetrahydrofuran (40 ml) keeping the temperature between -15 ² C and -9 ² C. The mixture was stirred between -15 ² C and -9 ⁹ C, under argon, for 45 minutes and then allowed to warm up to 20-C. The reaction was quenched by the addition of saturated aqueous ammonium chloride (50 ml). The mixture was treated with diethyl ether (50 ml). The organic layer was separated, washed with brine (50 ml), dried over magnesium sulfate and evaporated, yielding a yellow oil which was subjected to flash chromatography on silica gel using a mixture as eluent. of petroleum ether (p. eb, 4O-6O ^and C) and diethyl ether (3: 1 v / v), obtaining (E) -3- (3 —isopropyl-l-phenylpyrrole_C2, l-aj7is oquinolin-2-one i) to pre opiona acetate (2.66 g) as colorless solid, mp 145-146 ² c. / “Elementary analysis: C, 81.5; H, 6.61; N, 3.58%; Calculated: C, 81.4; H, 6.57; N, 3.7%; NMR (in CDC1 ₃ ): 1.24 (3H, t, J = 7Hz), 1.56 (6H, d, J = = 7Hz), 3.78 (IH, septet, J = 7Hz), 4.16 (2H, q, J = 7Hz), 5.42 (IH, d, J = 16Hz), 6.73 (IH, d, J = 8Hz), 7.02-7.58 (9H, m), 7 , 86 (IH, d, J = 8Hz), 7.89 (IH, d, J = 16Hz); Mass spectrum (electron impact) m / e = 383_j7.

(f) A solution of aluminum hydride and diisobutyl in ethylene (1.5 M; 16.8 ml) was added dropwise to a solution containing (Ξ) -3- (3-isopropyl-1-phenylpyrrole) / 72 l-a_ / 7isoquinolin-2-yl) propenoate (2.4 g) in tetrahydrofuran (50 ml) at 0 ⁹ C in an argon atmosphere. The mixture was stirred at 0 ° C for 30 minutes and the reaction stopped by the addition dropwise of aqueous saturated sodium sulfate solution (50 ml) at 0 0 C. ² resulting gel was then allowed to warm to 20 ^and C and then treated with sufficient aqueous hydrochloric acid (2 N) to dissolve the gel. The organic phase was separated and extracted

073

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Case 1111 / PT

aqueous phase with diethyl ether (50 ml). The organic solutions were added, washed with brine, dried over magnesium sulfate and evaporated, yielding (E) -3- (3-isopropyl-1-phenylpyrrole ZT2,1-a% 7is oquinolin- 2-i 1) propen-ol in the form of orange oil (2.14 g).

(g) A mixture of activated manganese dioxide (17.4 g), (E) -3- (3 — is opyl-1-phenylpyrrole / T 2, 1-a / 7 isoquinolin-2-yl) l-ol (2.14 g) and anhydrous diethyl ether (50 ml) ^and stirred at 20 C under argon for 17 h. The suspension was then filtered and the filtrate was evaporated to obtain a red-orange oil. The oil was triturated with a mixture of petroleum ether (p. Eb. 4O-6O ⁹ C) and diethyl ether (1: 1 v / v).

The resulting solid crystalline substance was collected, washed with a mixture of petroleum ether (p. Eb. 40-60 ^ 0) and diethyl ether (1: 1 v / v) and dried, obtaining ο (Ξ) - 3- (3-isopro pil-1-phenylpyrrole / 72, 1-ja / 7isoquinolin-2-yl) propene 1 (1.8 g), in yellow solid form, mp indistinct approximately

170 ⁹ C. / NMR (emCDCl ₃ ): 1.6 (6H, d, J = 7Hz), 3.76 (IH, srptet, J = 7Hz), 5.72 (IH, dd, J = 8Hz and 16Hz ), 6.75 (IH, d, J = 8Hz), 7.0-7.6 (9H, m), 7.15 (IH, d, J = 16Hz), 7.82 (IH, d, J = 8 Hz), 9.43 (IH, d, J = 8 Hz); Mass spectrum, m / e = 340 (M + H ⁺ ) / 7.

(h) A dispersion of sodium hydride in oil (80%, 12 mmol) was washed with hexane and then dried under an argon stream. Sodium hydride was suspended in dry tetrahydrofuran (40 ml) and stirred at -1O ⁹ C under an argon atmosphere. He was then added drop by drop acetoacetate (1.23 g) at -10 ⁹ C and the mixture was stirred for 30 minutes. Was then added dropwise at -10 ⁹ C, a solution of butyllithium in hexane (6.2 ml;

1.6 M) and the mixture was stirred for 15 minutes. A solution of (E) —3- (3-isopropyl — 1 — phenyl— pyrrole / 72,1-aJ7isoquinolin-2-yl) propylene (1.8) was added dropwise at -1O ⁹ C g) in tetrahydrofuran (8 ml) and the mixture was stirred for 1 hour. Quench the reaction at -1O C ⁹ by addition of saturated aqueous ammonium chloride and the mixture allowed to warm to 2O ⁹ C. was separated organic layer was evaporated in vacuo, and parti6 8073

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Case 1111 / PT

-35 the residue was taken up in diethyl ether (100 mH and water (100 ml). The ethereal solution was separated and the aqueous phase was extracted with diethyl ether (50 ml). The ethereal solutions were added, washed brine, dried over magnesium sulfate and evaporated in vacuo to give an orange oil which was subjected to flash chromatography “on silica gel using a mixture of petroleum ether (p. eb. 40-60 ^and C) and diethyl ether, obtaining (E) -5-hydroxy — 7— (3-isopropyl— -1-phenylpyrrole / ^- 2,1 — a_ / 7isoquinolin-2 - yl) -3 - methyl oxo-hept-6-enoate (1.4 g) in the form of yellow gum. / —RNN (in CDC1 ₃ ): 1.50 (6H, d, J = 7Hz), 2.48 ( IH, broad s), 2.54-2.6 (2H, m), 3.45 (2H, s), 3.64 (IH, septet, J = 7Hz), 3.74 (3H, s), 4.54 (IH, m), 5.21 (IH, dd, J = 16Hz and 6Hz), 6.64 (IH, d, J = 16Hz), 6.70 (IH, d, J = 8Hz), 7.0-7.54 (9H, m),

7.83 (IH, d, J = 8 Hz) / 7.

REFERENCE EXAMPLE 2

Proceeding in a manner analogous to that described in Reference Example 1 (h), but replacing the methyl acetoacetate used as a starting material with an appropriate amount of ethyl acetoacetate, (E_) - 5 — hydroxy — 7 was prepared -

- Ethyl (3-is opropi1-1-phenylpyrrole / ~ 2, la / 7is oquinolin-2-yl) -3-oxo-hept-6-enoate (7.34 g), in the form of yellow oil clear. // NMR (in CDC1 ₃ and D ₂ 0): 1.26 (3H, t, J = 7Hz), 1.50 (6H, d, J = 7Hz), 2.53-2.59 (2H, m ), 3.43 (2H, s), 3.64 flH, septet, j = 7Hz), 4.20 (2H, q, J = 7Hz), 4.54 (IH, m), 5.22 (IH , dd, J = 16Hz and 7Hz), 6.64 (IH, dd, J = 16Hz and 1Hz), 6.70 (IH, d, J = 8Hz), 7.0-7.54 (9H, m) , 7.83 (IH, d,

J = 8Hz) J7.

REFERENCE EXAMPLE 3

A solution of ethyl (Ej-5-hydroxy — 7- (3-isopropyl-1 — phenyl— pyrrole // 2, l-a_27isoquinolin-2 — yl) -3-oxo-hept — 6-enoate (0.94 g) prepared as in Reference Example 2 in ethanol (42 ml), it was reduced catalytically, in an atmosphere of

073

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Case 1111 / PT

-36drogen using 5% w / w palladium on carbon (0.254 g) and 5 ° w / w palladium on calcium carbonate (0.226 g) as catalysts. The mixture was filtered to remove the catalysts and the filtrate was evaporated, yielding 5-hydroxy-7- (3-is opi 1-1-phenylpyrrol / 7 2, l-a_27isoquinolin-2 - yl) Ethyl-3-oxo-heptanoate (0.98 g) as a light green gum.

REFERENCE EXAMPLE 4 (a) A mixture of benzoin (10.6 g), ethyl acetoacetate (8.1 g), aminoacetyldehyde dimethylacet1 (6.3 g), zinc chloride (13.8 g) and ethanol (100 ml ), was stirred at reflux for 40 hours. The mixture was then poured into water (800 ml) and stirred until a fine powder was formed. The product was separated by filtration, washed with water and dried in vacuo at 75 ° C, obtaining ethyl N- (2-dimethoxyethyl) -2,6 — diphenyl1-4-methylpyrrole — 3-carboxylate light yellow powder (18.08 g).

Concentrated sulfuric acid (100 ml) was treated with a suspension of N— (2-dimethoxyethyl) -2,6-diphenyl — 4-methyl — pyrrole-3-carboxylate fl8.0 g) in glacial acetic acid (15 ml) for 10 minutes, under agitation, keeping the temperature below 50 ° C by means of an ice bath, and the mixture was stirred in an ice bath for another 20 minutes. The mixture was then poured into a mixture of crushed ice (1 liter) with a solution of sodium hydroxide (95 g) in water (1 liter), and extracted with dichloromethane (3x500 ml). The combined extracts were washed with dilute aqueous sodium chloride solution, dried over a mixture of magnesium sulfate and charcoal and evaporated in vacuo. The resulting residue was crystallized from methanol, obtaining 3-methyl-1-phenylpyrrole / "2,1-is27-quinoline-ethyl 2-carboxylate (6.9 g), in colorless crystals, m.p. 119S-121SC. £ R.M.N. CDCD, · 0.91 (3H, t, J = = 7.5Hz), 1.81 (3H, s), 4.07 (2H, q, J = 7.5), 6.83 (lH, d ,

J = 4Hz), 7.10 (IH, dt, J = 1 and 4Hz), 7.16-7.56 (8H, m), 7.64 flH, d, J = 4Hz) _7.

073

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Case 1111 / PT

—3 7 -

Proceeding in a similar manner to that described in Reference Examples 1 (c) up to Kg), respectively, the following were prepared:

(b) 2-h idroximet i1-3-methyl-1-phenylpyrrole / 72,11-1'-oquinoline, as a solid wax.

(c) 3-methyl-1-phenyl oloj2 ~ 2, l-a_J7is oquinolin-2 —carbox at 1.dehyde, in yellow solid form, mp 174-179 ^and C. / “NMR (in CDC1 ₃ ) : 2.84 (3H, s), 6.90 (IH, d, J = 7Hz), 7.16 (IH, dt, J = = 2 and 8Hz), 7.30 (IH, dt, J = 2 and 8Hz), 7.40-7.60 (7H, m),

7.67 (IH, d, J = 7Hz), 9.79 (IH, s) J7.

(d) (E) -3- (3-methyl-1-phenylpyrrole / T2, 1-α-27isoquinolin-2-yl) ethyl propenoate, bright yellow solid form, mp 148-1529C. Z7R.M.N. (in CDCl): 1.14 (3H, t, J = 7Hz), 2.63 (3H, s), 4.16 (2H, q, J = 7Hz), 5.63 (IH, d, J = 16Hz), 6.79 (IH, d, J = 7Hz), 7.10 (IH, dt, J = 2 and 8Hz), 7.18-7.65 (8H, m), 7.62 (IH, d, J = 7 Hz), 7.76 (IH, d, J = 16 Hz) 7.

(e) (E) -3 - (3-methyl-1-phenylpyrol-C-2, 1-al-oquinolin-2-yl) propen-1-ol, in the form of oil; and (f) (E) —3 - (3-methyl-1-phenylpyrrole / T 2, l-7 is oquinolin-2-yl) propenal, yellow solid, mp 151-155ec. £ NMR (in CDC1 ₃ ): 2.64 (3H, s), 6.01 (IH, dd, J = 8 and 15Hz), 6.82 (IH, d, J = 8Hz), 7.11 (IH , dt, J = 2 and 8Hz), 7.20-7.65 (10H, m), 7.61 (1H, d, J = 8Hz), 9.41 ίIH, d, J = 8Hz) J7.

(g) By proceeding in a similar manner to that described in Example 1 (h), but using ethyl acetoacetate instead of methyl acetoacetate, (E) -5-hydroxy-7— (3-methyl-1-phenylpyr) was prepared - roll / “2, l-ay7isoquinolin-2-yl) —3 —oxo-hept — ethyl 6-enoate as an oil.

REFERENCE EXAMPLE 5 fa) A mixture of methyl propionylacetate (85.7 g), 4-fluorobenzaldehyde (81.7 g), piperidine (6 ml), glacial acetic acid (15 ml) and toluene (400 ml), was stirred under reflux

X

073

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Case 1111 / PT

X '

-3 8 for 18 hours, with drying using a Dean & distillation gourd. Stark. The cooled mixture was diluted with diethyl ether, washed with dilute aqueous sodium chloride solution and with water, and dried over magnesium sulfate. The solution was concentrated in vacuo and the residue was distilled to obtain a mixture of methyl 2 - (4-fluorobenzyl. Lidene) -3-oxopentanoate syn- and anti-isomers (114 g), as a light yellow oil, e.g. eb. 1082C / O, 15 mmHg — 140 ^and C / 0.4 mmHg. ^ Elementary analysis: C, 65.9; H, 5.60; F, 8.05%; Calculated: C, 66.1; Η, 5.55; F, 8.04%; IV 1727, 1705, 1672, 1625, 1601, 1263, 1233, 1231, 1196, 1162, 837 cm ^-1 ; NMR (in CDC1): 0.90 and 0.96 (3H, two triplets, J = 7Hz), 2.59 and 2.76 (2H, two quartets, J = 7Hz), 3.82 and 3.85 ( 3H, two angles), 7.00 -

-7.16 (2H, m), 7.28-7.52 (2H, m), 7.57 and 7.67 (IH, two molecules) _% 7.

(b) A mixture of methyl 2- (4-fluorobenzylidene) -3-oxo-pentanoate (52.0 g), benzaldehyde (25.4 g), triethylamine (22 g), 3,4-dimethyl iodide 5- (2-hydroxyethyl) thiazolium (6.3 g) and ethanol (100 ml), was heated under reflux in a nitrogen atmosphere for 16 hours. The cooled mixture was diluted with dichloromethane, washed with dilute hydrochloric acid (2 N), with dilute aqueous sodium bicarbonate solution and with water, and dried over magnesium sulfate. The solution was concentrated in vacuo and the residue was dissolved in hot methanol. The resulting off-white solid was filtered off, yielding methyl 2- (1-oxopropyl) -3- (4-fluorophenyl) —4 — pheni1-4-oxo-butanoate (21, 5 g), mp 1O4-1O9 ⁹ C. / ^ “Elemental analysis: C, 70.1; H, 5.42; F, 5.58%; Calculated:

C, 70.15; H, 5.60; F, 5.55%; I.V. 1749, 1738, 1716, 1708,

1679, 1508, 761, 697 cm ^-1 ; / NMR (in CDC1 ₃ ): 0.81 and 1.08 (3H, two triplets, J = 7Hz), 1.80-2.04 and 2.46-2.80 (2H, two sets of multiplets), 2.53 and 3.60 (9H, two singles), 4.58 and 4.62 (IH, two doublets, J = 10Hz), 5.39 and 5.42 (IH, two doublets, J = 10Hz), 6.96 (2H, t, J = 8Hz), 7.207.60 (5H, m), 7.90-8.00 (2H, m) J7.

(c) An aminoacetIdeidodimethylacet1 solution (8.55 g)

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / EN — 3 9 - and 2- (1-oxopropyl) -3- (4-fluorophenyl) -4-phenyl-4-oxobutanoate (25.3 g) in glacial acetic acid (240 ml), was I heated under reflux in a nitrogen atmosphere for 16 hours. After cooling, the solution was added, slowly and with stirring, to sulfuric acid (120 ml), maintaining the temperature below 152 ° C by means of an ice bath. After the addition, the solution was stirred for another 30 minutes and then poured into water, obtaining a brown solid substance. This was separated by filtration and subjected to chromatography on a column of silica gel, using as a eluent a 1: 2 v / v mixture of petroleum ether (p. Eb. 60-80 ^and C) and diethyl ether, obtaining the 1- (4-fluorine of eni 1) -3-ethylpyrrole / ^- 2,1,1-methyl-2-carboxylate methyl, (5.8 g). ^ // NMR (in CDCl ^): 1.31 (3H, t, J = 7Hz), 3.31 (2H, q, J = 7Hz), 3.62 (3H, s), 6.82 (IH , d, J = 8Hz), 7.00-7.42 (7H, m), 7.49 (1H, dd, J = 2 and 8Hz), 7.69 (IH, d, J = 8Hz) Σ7.

Proceeding in a similar way to Reference Examples 1 (c) to 1 (h), the following are prepared, respectively:

(d) 2-hydroxymethyl-3-ethyl-1- (4-fluorophenyl) pyrrole / ^- 2, 1-7 isoquinoline, in the form of thick oil.

(e) 3-ethyl-1- (4-fluorophenyl) pyrrole / 72,1-alpha-isoquinoline-2-carboxaldehyde in solid, yellow form.

(f) (E) -3- (3-ethyl-1- (4-fluorophenyl) pyrrole ^ T2, 1-α-7isoquinolin-2-yl) ethyl propenoate in solid, charged yellow, mp 142-144 ° C. / NMR (in CDCl ₃ ): 1.25 (3H, t, J = = 7Hz), 1.34 (3H, t, J = 7Hz), 3.10 (2H, q, J = 7Hz), 4, 18 (2H, q, J = 7Hz), 5.62 (IH, d, J = 16Hz), 6.78 (IH, d, J = = 8Hz), 7.05-7.56 (8H, m) , 7.66 (1H, d, J = 8Hz), 7.71 (IH, d, J = 16Hz) / 7.

(Çf) (E) -3 - (3-eth 1-1- (4-fluorophenyl) pyrrole / 72, 1-7 -isoquinolin-2-yl) propen-1-ol as a gum, and (h) (E ) -3 - (3-et 11-1- (4-fluorophenyl) pyrrole / 72, l-a__7is oquinolin-2-yl) preoperative 1 in yellow-orange solid form.

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

-4 0 - / “NMR (in CDC1 ₃ ): 1.34 (3H, t, J = 8Hz), 3.14 (2H, q, J = = 8Hz), 6.02 (1H, dd, J = 8 and 16 Hz), 6.83 (1H, d, J = 7Hz), 7.04-7.60 (9H, m), 7.69 (1H, d, J = 7Hz), 9.43 (1H , d, J = = 8 Hz) _7.

(i1 By proceeding in a similar manner to Reference Example 1 (h) but using ethyl acetoacetate instead of methyl acetoacetate, (E) -5-hydroxy-7- (3-ethyl-l- ( 4-fluorophenyl) pyrrolo / 7 ^2, 1-aJ7isoquinolin-2-yl) -3-oxo-hept-6-enoate // NMR (in CDC1 _3.): 1.20-1.35 (6H, m ),

2.70 (2H, m), 3.04 (2H, q, J = 7Hz), 3.47 (2H, s), 4.22 (2H, q, J = 7Hz), 4.59 (1H, q, J = 6Hz), 5.44 (1H, dd, J = 6 and 16Hz), 6.52 (1H, dd, J = 2 and 16Hz), 6.75 (1H, d, J = 8Hz), 7.00-7.45 (7H, m), 7.49 (1H, dd, J = 1 and 7Hz), 7.67 (1H, d,

J = 8Hz) //.

REFERENCE EXAMPLE 6 (a) Proceeding analogously to Reference Example 1 (a) but replacing 1-cyano-2-isobutyryl-1,2-dihydroisoquinoline, used as a starting material, with an appropriate amount of 1-cyano-2- (4-fluorobenzoyl) -1,2-dihydroisoquinoline, 1-amino-3- (4-fluorophenyl) oxazole // 4,3-a / 7isoquinoline tetrafluoroborate was prepared in solid form amare la, mp 198-2OO ⁹ C (with decomposition) // Elemental analysis: C55.8 Η-3.35 N — 7.6%; Calculated: C — 55.8 H-3.3 N-7.7% _ / 7.

(b) Proceeding in a similar manner to Reference Example 1 (b) but replacing ethyl phenylpropiolate, used as a starting material, with an appropriate amount of methyl 4-methylpent-2-inoate and using as an al solvent, 3-d_i methylimidazolin-2-one, methyl 3- (4-fluorophenyl) -1-isopropylpyrrole // 2tl-a_ ⁷ isoquinoline-2-carboxylate methyl, colorless solid, mp 114-115SC / “Analysis elementary: C, 76.1; Η, 5.53; N, 3.8%; Calculated: C, 76.5; H, 5.54; N, 3.9%; // NMR (in CDCip: 1.55 (6H, d, J = 7Hz), 3.69 (3H, s), 4.01 C1H, septet, J = 7Hz), 6.63 (1H, d, J = 8Hz), 7.12-7.56 (8H, m), 8.25 (1H, d, J = 8Hz), Mass spectrum

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

-41 «</ (electron impact) m / e

6l7 <

Proceeding in a manner similar to that described in Reference Examples 1 (c) to 1 (h), the following were prepared, respectively:

(c) 2-hydroxymethyl 1-1- isopropyl1-3- (4-fluorophenyl) pyrrole // 2,1-α-7isoquinoline, in colorless solid form, mp 121-1232 ° C. /7R.MN (in CDC1 ₃ and D ₂ 0): 1.62 (6H, d, J = 7Hz),

4.03 <1H, septet, J = 7Hz), 4.71 (2H, s), 6.60 (1H, d,

J = 8Hz), 7.16-7.60 (8H, m), 8.25 (1H, d, J = 8Hz); Mass spectrum (electron impact 'm / e - 333/7.

(d 1 1-isopropyl1-3 - (4-fluoropheni1) pyrrole // 2,1-a / 7isoquinoline-2 — carboxaIdehyde, yellow solid, mp 176-1785C // NMR (in CDC1 ₃ ): 1.60 (6H, d, J = 7Hz), 4.18 (1H, septet, J = 7Hz), 6.69 (1H, d, J = 8Hz), 7.11 - 7.53 (8H, m), 8 , 32 (1H, d, J = 8Hz), 9.92 (1H, s); Mass spectrum (electron impact) m / e = 331/7;

(e) (Ξ) -3- (1-is opr opi 1-3 - (4-fluorophenyl) pyrrole // 2, 1-a / 7isoquinolin-2-yl) ethyl propenoate, in light yellow solid form , mp 186-1882C / “NMR (in CDCl-j): 1.26 Γ3Η, t,

J = 7Hz), 1.58 (6H, d, J = 7Hz), 4.06 (1H, septet, J = = 7Hz), 4.17 ^ 2H, d, J = 7Hz), 5.55 (1H, d, J = 16Hz),

6.59 (1H, d, J = 8Hz), 7.18-7.53 (8H, m), 8.05 (1H, d, J = = 16Hz), 8.25 (1H, d, J = 8Hz); Mass spectrum (electron impact) m / e = 401 ^:

(f) (E) —3 - (l-isonropyl-3- (4-fluorophenyl) pyrrole / ~ 2,1-a / 7isoquinolin-2-yl) propen-l-ol, as a yellow, viscous oil // NMR (in CDCl ₃ ): 1.55 (6H, d, J = 7Hz), 4.01 (1H, septet, J = 7Hz), 4.11 (2H, dd, J = 1Hz and 6Hz), 5.49 (1H, d,

J = 6 and 16Hz), 6.54 (1H, d, J = 8Hz), 6.80 (1H, d, t, J = 1 and 16Hz), 7.1-7.51 (8H, m), 8.23 (1H, d, J = 8 Hz) / 7;

(g) (E) -3- (1-isopropyl1-3- (4-fluorophenyl) pyrrole // 2, isoquinolin-2-yl) propenal, yellow solid, mp 157160 ⁹ C // NMR (in CDC1 ₃ ): 1.62 (6H, d, J = 7Hz), 4.13 (1H, septet, J = 7Hz), 5.92 (1H, dd, J = 8 and 16 Hz), 6.64 (1H,

073

Ref: PAT / BQ / CH. / 644 / E Case 1111 / PT

-42d, J = 8Hz), 7.2-7.57 (8H, m), 7.86 (IH, d, J = 16 Hz), (IH, d, J = 8Hz), 9.48 (1H, d, J = 8 Hz) / ?.

(h) By proceeding in a similar manner to Reference Example 1 (h> but using ethyl acetoacetate instead of methyl acetoacetate, (Ξ) -5-hydroxy-7-fl-isopropyl-3- ( 4 — fluor of enyl) pyrrole / ^- 2, la / 7 isoquinolin-2-yl) -3 -oxo-hept-6-enoate, as a yellow viscous oil // NMR (in CDCl4): 1.28 IH, t, J = 7Wz), 1.5 * (6H, d, J = 7Hz), 2.58-2.63 (2H,

m), 3.43 (2H, s / 4.01 (IH, septet, J = 7Hz), 4.22 (2H, q, J = 7Hz), 4.61 (IH, m), 5.28 ( IH, dd, J = 7 and 16Hz), 6.55 (IH, d, J = 8Hz), 6.85 (1H, dd, J = 1 and 16Hz), 7.14-7.52 (8H,

m), 8.24 (IH, d, J = 8 Hz) / 7.

REFERENCE EXAMPLE 7

(a) By proceeding in a similar manner to Reference Example 1 (b) but replacing the ethyl phenylpropiolate, used as the starting material, with an appropriate amount of methyl 4-fluorophenylpropiolate, the l- (4-fluorophenyl) -3-isopropylpyrrole / ^- 2, 1 la / 7isoquinoline-2-carboxylate, in colorless solid form, mp 17O-1722C // Elemental analysis: C, 76.5; H, 5.7; N, 3.9%; Calculated: C, 76.5; H, 5.54; N, 3.9 ^ 7; / NMR (in CDCl ₃ ): 1.5l (6H, d, J = 7Hz), 3.58 (3H, s), 4.11 (IH, septet, J = 7Hz), 6.76 (IH, d , J = 8Hz), 7.03-7.52 (8H, m), 7.84 (1H, d, J = 8Hz); Mass spectrum (electron impact) m ^z e = 36/7 ·

Proceeding similarly to Reference Examples 1 (c) to 1 (h), the following were prepared respectively:

(b) 2-hydroxymethyl-3-isopropyl1-1- (4-fluorophenyl) pyrrole / 7 2, 1/7 _is oquinoline, as a light yellow gum. / ~ NMR (in CDCl ^ and D ₂ O): 1.52 (6H, d, J = 7Hz), 3.58 (IH, septet,

J = 7Hz), 4.54 (2H, s), 6.71 (IH, d, J = 8Hz), 7.02-7.50 (8H, m), 7.79 (IH, d, J = 8Hz) / 7;

(c) 3-isopropyl1-1- (4-fluorophenyl) pyrrole // 2, 1-6 / 7isoquin68 073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

FS

JX '

-43Calculated; C, 79.7; H, 5.5; N, 4.2%; R.M.N. (in CDCip (6H, D, J = 7Hz), 4.16 (1H, lino-2-carboxaIdehyde, light yellow solid, mp 145-1462C; // Elemental analysis: C, 79.8; H, 5 , 6, N, 4.3%;

1.53 septet, J = 7Hz), 6.82 (IH, d, J = 8Hz), 7.08-7.53 (8H, m), 7.87 (1H, d, J = 8Hz), 9 , 78 (IH, s); Mass spectrum (impact by electrSol m / e = = 331/7;

(d) (8) -3- (3-is opropi1-1- (4-fluorophenyl) pyrrole // 2,1-a / 7isoquinolin-2-yl) ethyl propenoate, light yellow solid, mp 151 -1532C // Elemental analysis: C, 77.5; H, 6.25; N, 3.3%; Calculated: C, 77.8; H, 6.03; N, 3.5%; NMR (in CDC1 ₃ ): 1.16 (3H, t, J = 7Hz), 1.56 (6H, d, J = 7Hz), 3.67 (IH, septet, J = 7Hz), 4.17 ( 2H, d, J = 7Hz), 5.42 (IH, d, J = 16Hz), 6.72 (1H, d, J = 8Hz), 7.03-7.52 (8H, m), 7, 84 (IH, d, J = 8Hz), 7.87 (IH, d, J = 16Hz); Mass spectrum (electron impact) m / e = 40 l / 7;

(e) (E) -3- (3 —isopropyl-1 ~ (4-fluorophenyl) pyrrole // 2, 1-ã / isoquinolin-2-yl) propen-1-ol, as a yellow oil / “NMR ( in CDC1 ₃ and D ^ ⁰ ) ^: 1/51 (6H, d, J = 7Hz), 3.67 (IH, septet, J = 7Hz), 4.1 (2H, dd, J = 1Hz and 6Hz), 5.48 (IH, d, t,

J = 6 and 16Hz), 6.58 (IH, d, t, J = 1 and 16Hz), 6.69 (IH, d,

J = 8Hz), 7.02-7.50 (8H, m), 7.83 (IH, d, J = 8Hz); Mass spectrum (electron impact) m / e = 359/7;

(f) (E) -3- (3-isopropyl-1- (4-fluorophenyl) pyrr010 / -2, la / 7isoquinolin-2-yl) propenal, yellow solid mp 1551572C // Elemental analysis; C, 80.5; H, 5.72; N, 3.9%; Calculated; C, 80.6; H, 5.64; N, 3.9%; NMR (in CDC1 ₃ ): 1.60 (6H, d, J = 7Hz), 3.78 (IH, septet, j = 7Hz), 5.78 (IH, dd,

J = 8 and 16Hz), 6.77 (1H, d, J = 8Hz), 7.05-7.54 (8H, τη), 7.62 (IH, d, J = 16Hz), 7.84 ( 1H, d, J = 8Hz), 9.41 (IH, d, J = = 8Hz); Mass spectrum (electron impact) m / e = 357/7.

(g) By proceeding in a similar manner to Reference Example 1 (h) but using ethyl acetoacetate instead of methyl acetoacetate, (E_) —5-hydroxy-7- (3-isopropyl-1) was prepared - (4-fluorophenyl) pyrrole / ^- 2,1-a / 7 is oquinolin-2-yl) -3-oxo-hept-

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

-6-ethyl enoate, in the form of light yellow gum. // NMR (in CDC1 ₃ and D ₂ 0): 1.26 (3H, t, J = 7Hz), 1.49 (6H, d, J = 7Hz), 2.56-2.64 (2H, m ), 3.43 (2H, s), 3.62 (IH, septet, J = 7Hz), 4.20 (2H, q, J = 7Hz), 4.48-4.6 (IH, m), 5.22 (1H, dd, J = 7 and 16Hz), 6.63 (IH, d, J = 16HZ), 6.69 (IH, d, J = 8Hz), 7.01-7.80 (8H , m), 7.81 (IH, d, J = 8Hz) “7.

REFERENCE EXAMPLE 8 (a) A stirred solution of methyl 2-phenyl-2-bromoacetate (53.8 g) in acetonitrile (450 ml) was treated with triethylamine (45.2 ml). The mixture was then cooled ge_ it bath and treated dropwise over 15 minutes with a solutio of the aminoaceta Ideídodimetilaceta1 (37.8 ml) in acetonitrile (80 mM, keeping the temperature below 45 C. Stir ⁹ the mixture was left at room temperature for 2 hours and then left to stand for 48 h. The mixture was diluted with diethyl ether (800 ml) and washed with water (3x250 ml). The ethereal layer was dried over magnesium sulfate and evaporated, yielding methyl 2- (2,2-dimethoxyethylamino) phenylacetate (55.5 g), as a colorless oil // NMR (in CDCl ₃ ): 2.10 (IH, b), 2.57-2.79 (2H, m), 3.34 (3H, s), 3.37 (3H, s), 3.68 (3H, s), 4.50 (IH, t , J = 6 Hz), 7.35 (5H, m) _ / 7.

(b) A solution of methyl 2- (2,2-dimethoxyethylamino) phenylacetate (55.0 g) and triethylamine (36.5 ml) in dichloromethane (450 ml), was treated with a solution of isobutyryl chloride (25 ml) in dichloromethane (150 ml) in order to maintain a smooth flow. The pink mixture was stirred at room temperature for 2 h and then washed with water (250 ml), diluted hydrochloric acid (0.5 N, 300 ml), water (25 ml), aqueous sodium hydroxide solution ( 0.5 N; 300 ml) and then with water (2x250 ml), dried over magnesium sulfate and evaporated, yielding 2-phenyl-2 - ^ / tf- (2,2-dimethoxy il) -2-methylpropanami / methyl acetate, as a light red oil. / ~ NMR (in CDC1> ₃ : 1.14 (6H, d, J = 7Hz), 3.10-3.30 (7H, m), 3,363.44 (2H, m), 3.54 (IH, t, J = 6 Hz), 3.75 (3H, s), 6.07 (IH, s), 7.22-7.46 (5H, m) _7.

073

Ref: PAT./BQ/CH/644./E

Case 1111 / PT

-4 5-F £ (c) A solution of 2-phenyl-2 - / n- (2,2-dimethoxyethyl) -2-methyl propanamido / methyl acetate (72.3 g ) in methanol (800 ml), was treated with a solution of sodium hydroxide (30 g) in water (200 ml). The mixture was stirred for 2.5 h and left to stand at room temperature for 18 h. Concentrated to 500 ml and diluted with water (500 ml), washed with diethyl ether (2x200 ml), cooled to below 10 ^and C and acidified with hydrochloric acid (4N), maintaining at a temperature below 10 ⁹ C. The precipitated product was extracted with ethyl acetate (3x75o ml) and the extracts together were washed with brine (300 ml) and evaporated to give an off-white solid substance which was crystallized from a mixture of ethanol and ethyl acetate, and washed with petroleum ether, obtaining 2-pheni1-2- (N- (2,2-dimethoxyethyl) -2-methylpropanamido) acetic acid (67.2 g) as a white solid mp 147-149 ° C ² - Elemental analysis: C-62.3 H-7.6 N-4.54%; Calculated: C-62.1 H-7.4 N-4.53% 77.

(d) A suspension of 2-phenyl-2 - ^ - (2,2-dimethoxyethyl) -2-methylpropanamido-acetic acid (32.1 g) and methyl 4-fluorophenylpropiol (22.5 g) in acetic anhydride (120 ml), was treated with triethylamine (16 ml) and the resulting amber solution was stirred at room temperature in an argon atmosphere for 24 h. The solution was then added dropwise over 10 minutes to concentrated sulfuric acid (200 ml), stirring and cooling in an ice bath. The mixture was stirred for 30 minutes, then poured into ice water (2.5 l) and extracted with dichloromethane (3x400 ml). The combined extracts were washed with water (250 ml) and brine (25 ml), dried over magnesium sulfate and evaporated to give a solid substance. of the chestnut that was crystallized in methanol, obtaining the methyl 1— - (4-fluorophenyl) -3-isopropylpyrrole / 72, 1 ° ^{s s} <<3'-iinoline-2-carboxylate, of off-white solid form, mp 170-173 sc.

The present invention includes within its scope the preparation of pharmaceutical compositions comprising at least one of the compounds of formula I or a pharmaceutically salt thereof.

073

Ref: PAT / BQ / CH / 644 / E

Case 1111 / PT

-4 6acceptable in association with a pharmaceutically acceptable vehicle or coating. In clinical practice the compounds of the present invention can be administered parenterally, but are preferably administered rectally or, even more preferably, orally.

Solid compositions for oral administration include tablets, pills, powders and granules. In these solid compositions one or more of the active ingredients will, or are, mixed with at least one inert diluent such as starch, sucrose or lactose. The compositions may also comprise, as in normal practice, additional substances other than inert diluents, e.g. ex. lubricating agents such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, suspensions, solutions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. In addition to inert diluents, these compositions may comprise adjuvants, such as wetting and suspending agents, sweeteners, flavorings, perfumes and preservatives. Compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more active substances with or without the addition of diluents or excipients.

Preparations according to the invention intended for parenteral administration include sterile, aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. Those with positions can also contain adjuvants such as stabilizing agents, preservatives, wetting agents, emulsifiers and dispersants. They can be sterilized, e.g. eg by filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiation or by heating. They can also be produced in the form of solid sterile compositions that can be dissolved in sterile water or any—

073

Ref: PAT / BQ / CH / 644 / E

Case 1111'PT

-4 7 any other sterile injectable medium, immediately before use.

Solid compositions for rectal administration include swabs formulated according to known methods and containing one or more compounds of formula I or a pharmaceutically acceptable salt thereof.

The percentage of active principle in the compositions of the invention may vary, and it is necessary that it constitutes such a proportion that an adequate dosage can be obtained. Obviously, several unit dosage forms can be administered at the same time. The dose used will be determined by the doctor and depends on the desired therapeutic effect, the route of administration, the duration of treatment and the condition of the patient. In the adult, the doses are generally between 0.1 to 50, ^z preferential copy 0.5-5 mg kg body weight per day, oral administration oara.

The following Example illustrates pharmaceutical compositions according to the present invention.

COMPOSITION EXAMPLE 1

Gelatin capsule of size N ⁹ 2 containing each:

2: 1 mixture of erythro diastereoisomers and (E) -3,5-dihydroxy-7- (3-isopropyl-1-phenylpyrrole-2, 1-a / 7isoquinolin-2-

-il) sodium hept-6-enoate 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg

were prepared according to the current method.

active ingredient may be replaced with an appropriate amount of any other compound of formula I.

073

Ref: PÂl / BQ / CH / 644 / Έ

073

VIII

Pef: ΡΑϊ / hQ / CH / 6 44 / E

Caee 111ΐ / ΗΓ -49-

R

IX

XI

-50XII

073

Te f: PAT / BQ / CH / 6 44 / E - /

Case 1111 / PT

BF

R ¹ C0 \

N ^N R ⁴

XVI

-51. <R

073

Pe f:? AT / BQ / CIí / S 4 4 / E Cnro 1111 / ??

XVIII

XX

R ¹ CO

XXIII

073

Eef: PAT / bQ / GH / 644 / E Case 1111 / PT

-52Z? &

R ⁴

XXIV

XXV

XXVII

XXVIII

.....

• Í? '

073

Ref: PAT / BQ / CH / 644 / E Case 1111 / PT

Claims (15)

1 - Process for the preparation of a pyrroloff2, 1-aj-isoquinoline derivative of the general formula: ~ 3 R 1 2 where R and R, which can be the same or different, each represent a cycloalkyl group containing 3 to 8 carbon atoms or represent a straight or branched chain alkyl, alkenyl or alkynyl group containing up to 6 carbon atoms , which can be substituted by up to 3 atoms of halo genus, or an optionally substituted aryl or heteroaryl group, X represents an ethylene or vinylene group, R4 represents a group of general formula: IZ .5 -Y-CH ₂ -CH (OH) -CH ₂ -COOR 'where Y represents a carbonyl or hydroxymethylene group and R' represents an hydrogen atom or an optionally substituted alkyl group containing up to 6 carbon atoms or R represents a ring general formula lactone OH 68 073 -54 ° ef: PAT'BQ / CH / 644 / E Case 1111 / PT and the R symbols can be the same or different and each represent a hydrogen or halogen atom or optionally represent an alkyl, alkenyl or alkali group substituted straight or branched chain containing up to 6 carbon atoms or an optionally substituted aryl or heteroaryl group or a group of formula R ^ o-, where R ^ represents a straight or branched chain alkyl group containing up to 6 carbon atoms, one aryl group or an aralkyl group containing 1 or 2 carbon atoms in the alkyl part and its pharmaceutically acceptable salts where R ⁵ represents a hydrogen atom characterized by comprising: z 3 a) when in formula I, R represents a group of formula II where Y represents a hydroxymethylene group and R represents an alkyl group, optionally substituted, containing up to 6 carbon atoms, the reduction of a compound of general formula IV 12 4 7 where R, r, R and X are defined as above and R represents a group of general formula V θ -CH (OH) -CH ₂ -CO-CH ₂ -COOR V g where R represents an optionally substituted alkyl group containing up to 6 carbon atoms; or b) when in formula I, R represents general mule II where R ³ represents an atom of a hydrogen group, form 68 073 Ref: PAT / BQ / CH / 644 / E & Case 1111 / PT ^Z ' -55- ’· 'the hydrolysis of a corresponding compound of formula I 5 where R represents an optionally substituted alkyl group containing up to 6 carbon atoms, to form a salt, optionally followed by acidification to form a carboxylic acid. c o; or c) when in formula I, R represents a group of formula II where Y represents a carbonyl group and R ³ represents an optionally substituted alkyl group, containing up to 6 carbon atoms, the oxidation of a corresponding compound of general formula I where Y represents a hydroxymethylene group; or d) when in general formula I, X represents an ethylene group, R ³ represents a group of formula II and R ³ represents an optionally substituted alkyl group, containing up to 6 carbon atoms, the catalytic hydrogenation of a corresponding compound of general formula I where X represents a vinylene group; or e) when in formula I, R represents a lactone ring of formula III, the cyclization of a corresponding compound of general formula I where R represents a group of formula li where Y represents 5 a hydroxymethylene group and R represents a hydrogen atom. Process according to claim 1, characterized in that the oxidation of point (c) is carried out by reaction with activated manganese dioxide. Process according to claim 1, characterized in that R and R are different, X represents a vinylene group in E configuration, the aryl groups are phenyl and the arylalkyl groups are benzyl or phenylethyl. Process according to claim 1 or 3, characterized in that the substituted alkyl, alkenyl or alkynyl groups contain, unless otherwise specified, 5668 073 Ref: PAT / BQ / CH / 644 / Ε Case 1111 / PT /? up to 3 substituents chosen from halogen atoms and straight or branched chain alkylthio and alkoxy groups, each containing up to 6 carbon atoms. Process according to claim 1, 3 or 4, characterized in that the substituted aryl and heteroaryl groups and parts contain one or more substituents chosen from halogen atoms, cycloalkyl and cycloalkenyl groups each containing 4 to 8 straight-chain or branched carbon atoms, straight or branched alkyl, alkenyl or alkynyl groups each containing up to 6 carbon atoms, hydroxy groups, alkoxy groups, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl and alkanyl, straight chain or branched, each containing up to 6 carbon atoms and optionally substituted heteroaryl and aryl groups. 6 - Process according to claims 1, 3 to 5, 1 2 characterized in that one between R and R represents an optionally substituted aryl or heteroaryl group and the other represents a cycloalkyl group, containing 3 to 8 carbon atoms or a straight or branched chain alkyl, alkenyl or alkynyl group, containing up to 6 atoms carbon, which can be replaced by up to 3 halogen atoms. Process according to claim 6, characterized in that R represents a substituted or unsubstituted phenyl group. Process according to claim 6 or 7, characterized in that R represents a phenyl group substituted by a halogen atom in position 4. Process according to claims 6, 7 or 8, characterized in that it represents a straight or branched chain alkyl group. Process according to claims 1, 3 to 9, 68 073 Ref: PAT / BQ / CH / 644 / E Case 1111 / PT -57characterized by Y represents a hydroxymethylene group. Process according to any of claims 1, 3 to 10, characterized in that R ³ represents a hydrogen atom or a methyl or ethyl group. 12 - Process according to 1, 3 to 11, characterized by all rem hydrogen atoms. any of the symbols claims 4 R represents Process according to claims 1, 3 to 12, characterized in that R ³ represents a group of formula II, Y represents a hydroxymethylene group and the compound is in the erythro form. Process according to claim 1, characterized in that the following compounds are obtained: (Ξ) -3,5-dihydroxy-7- (3 - is opyl-1-phenylpyrrol o-6 ~ 2,1-aVisoquinolin-2-yl) methyl, ethyl or sodium hept-6-enoate, (Ξ) -3-hydroxy-7- (3-is opropi1-1-phenylpyrrole-2,1-a-7isoquinolin-2-yl) -5-oxo-hept-6-enoate, acid (E. ) -3-hydroxy-7- (3-is opr opi 1-1-phenylpyrrole Z72, l-a__7iso quinolin-2-yl) -5-oxo-hept-6-enoic acid, 3,5-dihydroxy- 7- (3 - isopropyl-1-phenylpyrrole / ^- 2, la._7isoquinolin-2-yl) -heptanoic, (E) -3,5-dihydroxy-7- (3-methyl-1-phenylpyrrole / 72, Ethyl or sodium 1isoquinolin-2-yl) hept-6-enoate, (Ξ) -3,5-dihydroxy-7- (3-ethyl-1- (4-fluorophenyl) pyrrole / 7 ”2, l -a_7isoquinolin-2-yl) ethyl or sodium hept-6-enoate, (E) -3,5-dihydroxy-7-7 ~ l-is opropi1-3- (4-fluorophenyl) pyrrole / 7 * 2 ethyl or sodium l-a-Z'-isoquinolin-2-yl77-hept-6-enoate, (E) -3,5-dihydroxy-7 - // 3-is opropi1-1- (4-fluorophenyl) pyrrole / Ethyl or sodium 72,1-a oquinolin-2-i-hept-6-enoate, (E.) -3-hydroxy-7- / ~ 3-is opr opi 1-1- (4-flu orofenyl) pyrrole / 72, l-a_ / 7isoquinol ethyl or sodium in-2-ylJ7-5-oxo-hept-6-enoate 68 073 Ref: PAT./BQ/CH/644 / Ε Case 1111 / PT -58or the threo or erythro forms of the 3,5-dihydroxy compounds, or a mixture of the threus and erythro forms; or 4-hydroxy-6- / 72 - (3 - isopropyl 1-1-phenyl-pyrroloZ / 2,1-a / 7is oquinol in-2-yl) et i 1 / 7-3, 4,5,6 -tetrahydro-2H-pyran-2-one or its isomeric or trans lactone ring isomers or a mixture thereof. Process for the preparation of a pharmaceutical composition, characterized in that a pyrrole derivative / 72,11-7isoquinoline or a pharmaceutically acceptable salt thereof prepared according to claim 1 is combined with a pharmaceutically acceptable diluent or carrier. Lisbon, _q ·;